Ring substituted pyrazino-isoquinoline derivatives and their preparation

ABSTRACT

Isoquinolines of the formula ##STR1## wherein R 1  is H, OH, alkyl; R 2  is H, or an unsubstituted or substituted carbonyl, carbonyloxy or thiocarbonyl group; R 3  is H, alkyl or hydroxy alkyl; R 4  is H, alkyl or phenyl; R 5  is O, H,H or H and alkyl, phenyl, halo or hydroxy; R 6  and R 7  are optional substituents; and R 8  is H or alkyl, R 2  being a thiocarbonyl or carbonyloxy group when R 1  and R 3  to R 8  are H and X is 0; and their physiologically acceptable salts, are antihelmintics, especially against cestodes and trematodes; some also possessing CNS activity, e.g., psychotropic and blood pressure regulating activity.

BACKGROUND OF THE INVENTION

This invention relates to novel ring-substituted 4-oxo- and4-thioxo-hexahydro-4H-pyrazino-[2,1-a]isoquinoline derivatives and theirpreparation. Similar compounds are described in GermanOffenlegungsschrift No. 1,470,062 and in U.S. Pat. No. application Ser.No. 533,467, now U.S.Pat. No. 4,001,411 granted Jan. 4, 1977.

SUMMARY OF THE INVENTION

The novel isoquinoline derivatives of this invention are compounds ofthe general Formula I: ##STR2## wherein R¹ is a hydrogen atom, hydroxyor alkyl; R² is a hydrogen atom or CYR⁹ ; R³ is a hydrogen atom, alkylor hydroxyalkyl; R⁴ is a hydrogen atom, alkyl or phenyl; R⁵ is an oxygenatom, two hydrogen atoms, or a hydrogen atom and one of alkyl, phenyl,halogen atom, or hydroxy; R⁶ and R⁷, which can be alike or different,each are a hydrogen atom, a halogen atom, hydroxy, amino, nitro, cyano,alkyl, alkoxy, acyloxy, monoalkylamino, dialkylamino, acylamino,benzoyloxy or the group Z; R⁸ is a hydrogen atom or alkyl; R⁹ is ahydrogen atom, alkyl of up to 6 carbon atoms or cycloalkyl orcycloalkenyl of 5 to 7 carbon atoms which is unsubstituted orsubstituted by oxygen or mono- or disubstituted by R¹⁰ and can beinterrupted in the ring by an oxygen atom, a sulfur atom, SO or SO₂, oris phenyl which is unsubstituted or mono- or disubstituted by R¹⁰ or Z,or is thienyl, pyridyl or R¹¹ ; R¹⁰ is a fluorine or chlorine atom,hydroxy, nitro, amino, monoalkylamino, dialkylamino or acylamino; R¹¹ isalkoxy, phenoxy or a cycloalkoxy of 5 to 7 carbon atoms, Hal is afluorine, chlorine, bromine or iodine atom, X and Y, which can be thesame or different, each is an oxygen or sulfur atom; Z is phenylazo ornaphthylazo which is unsubstituted or substituted by one or more ofhalogen, hydroxyl, amino, alkyl, alkoxy, monoalkylamino, dialkylamino,COOH and SO₃ H; alkyl, hydroxyalkyl, alkoxy and acyl unless otherwiseindicated being up to 4 carbon atoms; with the proviso that R² is CSR⁹or COR¹¹ when R¹ and R³ to R⁸, inclusive, each are hydrogen atoms and Xis an oxygen atom; and the physiologically acceptable salts thereof.

In a composition aspect, this invention relates to such novelisoquinolines. In another composition aspect, this invention relates toa pharmaceutical composition comprising in unit dosage form anantihelmintically effective amount of a novel isoquinoline of thisinvention in admixture with a pharmaceutically acceptable carrier.

In process aspects, this invention relates to processes for theproduction and use of such compositions.

DETAILED DESCRIPTION

The novel compounds of general Formula I and their physiologicallyacceptable salts possess, with good compatibility, valuableparasitological and other pharmaceutical activities. Thus, they are,inter alia, valuable anthelmintics and exhibit, in particular, a broadspectrum of activity against cestodes and trematodes. Some of the newcompounds exhibit in activity upon the central nervous system and, inparticular, possess psychotropic as well as blood pressure-influencingand especially blood pressure-lowering activities.

Additionally, some of the new compounds possess tranquilizing,adrenolytic and muscle-relaxant activities, which can be ascertained byconventional methods known for this purpose. These activities have beendetermined, for example, in mice, rats and rhesus monkeys.

The novel compounds of general Formula I and the physiologicallycompatible salts thereof can be used as pharmaceuticals in human andveterinary medicine, especially as anthelmintics, and also asintermediates for the preparation of other pharmaceuticals.

The alkyl, hydroxyalkyl, alkoxy and acyl values for R¹ through R¹¹ and Zeach are of up to 4 carbon atoms unless otherwise indicated, butpreferably they contain 1 or 2 carbon atoms. Thus, alkyl preferably ismethyl, but also can be ethyl, as well as n-propyl, isopropyl, n-butyl,isobutyl, sec.-butyl and tert.-butyl. Hydroxyalkyl is preferablyhydroxymethyl or 2-hydroxyethyl. Alkoxy is preferably methoxy, but canalso be ethoxy, as well as n-propoxy, isopropoxy, n-butoxy, isobutoxy,sec.-butoxy and tert.-butoxy. Acyl is preferably acetyl but can also beformyl, propionyl, n-butyryl and isobutyryl. The same also applies tothe groups derived from these radicals. Thus, monoalkylamino ispreferably methylamino, dialkylamino is preferably dimethylamino ordiethylamino, acylamino is preferably acetylamino and acyloxy ispreferably acetoxy.

In R⁹, alkyl can be of up to 6 carbon atoms and, in addition to theabove-mentioned values, can also be, for example, straight-chained orbranched pentyl and hexyl.

R¹ preferably is a hydrogen atom, hydroxy or methyl. R² is preferablyCYR⁹ but the compounds in which R² is a hydrogen atom are also ofimportance. R³ is preferably a hydrogen atom, methyl or 2-hydroxyethyl.R⁴ is preferably a hydrogen atom or methyl. R⁵ preferably stands for twohydrogen atoms or for one hydrogen atom and a methyl group. At least oneof R⁶ and R⁷ is preferably a hydrogen atom; other preferred values beingfluorine, chlorine, bromine, hydroxy, amino, nitro, methyl and methoxy.R⁸ preferably is a hydrogen atom or methyl.

R⁹ preferably is unsubstituted or substituted cycloalkyl of 5 or 6carbon atoms, especially unsubstituted or substituted cyclohexyl, aswell as unsubstituted or substituted phenyl. Especially preferredsubstituents on the cycloalkyl radical are oxygen, for example, in theform of a keto group, fluorine atoms, nitro, amino, methylamino,dimethylamino and acetylamino radicals, as well as chlorine atoms,ethylamino, diethylamino, formylamino and propionylamino. Preferredsubstituents on the phenyl radical are fluorine atoms, amino, nitro,methylamino, dimethylamino, formylamino and acetylamino, which arepreferably in the m or p-position but can also be in the o-position.Examples of other substituents on the phenyl radical are chlorine atoms,hydroxy, ethylamino, diethylamino, n-propylamino, propionylamino,n-butyrylamino and isobutyrylamino, which are preferably in the m- orp-position but can also be in the o-position. Other preferred values forR⁹ are 2- or 3-cyclohexenyl, thienyl attached at the 2- or 3-position,pyridyl attached at the 2-, 3- or 4-position, tetrahydropyranyl attachedat the 2-, 3- or 4-position, thiacyclohexyl attached at the 2-, 3- or4-position, which can be mono- or disubstituted on the sulfur atom byoxygen (especially thiacyclohexyl-4), cyclohexadienyl or R¹¹. R⁹ canalso be, for example, alkyl of up to 6 carbon atoms, cyclopentyl,cycloheptyl, 2- or 3-cyclopentenyl or 2-, 3- or 4-cycloheptenyl.

R¹⁰ is a fluorine atom, amino, methylamino, dimethylamino, formylamino,acetylamino or nitro. R¹¹ preferably is methoxy or cyclohexyloxy. Hal ispreferably fluorine and chlorine. Z preferably is 4-hydroxyphenylazo,4-methoxyphenylazo, 4-aminophenylazo, 4-methylaminophenylazo,4-dimethylaminophenylazo, naphthyl-1-azo or naphthyl-2-azo unsubstitutedor substituted in the 1- or 2-, 4-, 6-, 7-, 8-, or 9-position byhydroxy, alkoxy, amino, alkylamino, dialkylamino, COOH or SO₃ H.

Preferred compounds of this invention are, in particular, those ofgeneral Formula I and their acid addition salts in which at least one ofthese symbols has one of the above-given preferred values. Some of thesepreferred groups of compounds can be defined by the following partFormulae Ia to Is, which otherwise correspond to the above-given generalFormula I but wherein:

Ia: R¹ is hydrogen;

Ib: R² is hydrogen;

Ic: R² is COR⁹ ;

Id: R² is CS-alkyl, CS-cycloalkyl containing 5 or 6 carbon atoms orthiobenzoyl;

Ie: R³ is hydrogen;

If: R⁴ is hydrogen or methyl;

Ig: R⁵ represents two hydrogen atoms or a hydrogen atom and methylgroup;

Ih: R⁶ and R⁷ are hydrogen;

Ii: R⁸ is hydrogen;

Ij: R¹, R³, R⁶ to R⁸ each are hydrogen;

Ik: R¹ and R³ to R⁸ each are hydrogen and X is sulfur;

Il: R² is COR⁹ wherein R⁹ is alkyl or up to 4 carbon atoms, cyclohexylwhich is either unsubstituted or is substituted by an oxygen atom, oneor two fluorine atoms, methylamino or dimethylamino, or phenyl which iseither unsubstituted or substituted in the m or p-position by fluorine,amino, methylamino or dimethylamino, or tetrahydropyranyl orthiacyclohexyl attached at the 2- or 4-position;

Im: R² is COR⁹, R⁴ is methyl and R⁹ is phenyl, cyclohexyl,tetrahydropyranyl or thiacyclohexyl;

In: R² is COR⁹, R⁵ is methyl and R⁹ is phenyl, cyclohexyl,tetrahydropyranyl or thiacyclohexyl;

Io: R² is COR⁹, R⁴ or R⁵ is methyl and R⁹ is phenyl or cyclohexylsubstituted by nitro, amino or flurorine in the 3- or 4-position;

Ip: R¹ is hydrogen or hydroxy, R² is CYR⁹, R³ is hydrogen, methyl or2-hydroxyethyl, R⁴ is hydrogen or methyl, R⁵ represents two hydrogenatoms or a hydrogen atom and a methyl group, one of R⁶ and R⁷ ishydrogen, hydroxy or methoxy and the other is hydrogen, hydroxy, amino,nitro, chlorine, methyl or methoxy, R⁸ is hydrogen, R⁹ is alkyl of up to3 carbon atoms, cyclohexyl, oxocyclohexyl, tetrahydropyranyl,thiacyclohexyl, phenyl, fluorophenyl, aminophenyl, nitrophenyl, pyridyl,ethoxy, cycloexyloxy or phenoxy and X and Y, which can be alike ordifferent, are oxygen or sulfur atoms;

Iq: R¹ is hydrogen, R² is CYR⁹, R³ is hydrogen or methyl, R⁴ is hydrogenor methyl, R⁵ represents two hydrogen atoms, or a hydrogen atom and amethyl group, one of R⁶ and R⁷ is hydrogen and the other is hydrogen,amino, nitro or chlorine, R⁸ is hydrogen, R⁹ is alkyl of up to 3 carbonatoms, cyclohexyl, phenyl, fluorophenyl, aminophenyl, nitrophenyl orpyridyl and X and Y, which can be alike or different, are oxygen orsulfur atoms;

Ir: R¹ is methyl; and

Is: R² is thiacyclohexyl-4-carbonyl.

In a process aspect, this invention relates to processes for theproduction of compounds of general Formula I, and their physiologicallyacceptable salts, wherein

a. a compound of the general Formula

    Q--R.sub.2                                                 (II)

wherein Q is ##STR3## wherein E is a halogen atom, a hydroxy or afunctionally modified hydroxy, and R¹ to R⁸, Hal and X have the valuesgiven for general Formula I, is cyclized under conditions splitting offHE; or

b. a compound of the general Formula III ##STR4## wherein R¹² has thesame values as R⁵ or is alkylidene of up to 4 carbon atoms and R¹ to R⁸,X and Hal have the same values as given for general Formula I and thedotted lines mean that at one or more of these positions, a double bondcan be present, with the proviso that R¹² is alkylidene when nonethereof is a double bond, or a salt of said compound, is treated with areducing agent; or

c. a compound of the general Formula IV: ##STR5## wherein R¹³ is ahydrogen atom or COR¹⁴, R¹⁴ is a hydrogen atom, alkyl of up to 6 carbonatoms or a cycloalkyl or cycloalkenyl of 5 to 7 carbon atoms which iseither unsubstituted or is mono- or disubstituted by oxygen or by R¹⁰and/or interrupted in the ring by an oxygen atom or sulfur atom, SO orSO₂ or is phenyl which is either unsubstituted or is mono- ordisubstituted by R¹⁰ or Z, or is thienyl, pyridyl, and R¹⁰ and Z havethe values given for Formula I, is treated with a hydroxylating,hydroxyalkylating, halogenating or nitrating agent or with an agentgiving off sulfur; or

d. a compound of general Formula IV wherein R¹³ is a hydrogen atom, istreated with a thioacylating agent or with a compound of the generalformula R¹¹ --CO--E, wherein R¹¹ and E have the values given above; and,if desired, in the thus-obtained product, one or more of R¹ to R⁸ and Xare converted into another value thereof; and/or when the productobtained is a racemic compound, it is resolved into its opticalantipodes and/or a compound in free base form is converted into aphysiologically acceptable salt thereof with an acid or a base or into aquaternary ammonium salt and/or a free base of general Formula I isliberated from a thus-obtained acid addition salt thereof.

Otherwise, the above-described preparation of the compounds of thisinvention is achieved in a known manner by known methods, such as aredescribed in the literature (for example in standard reference works,such as Houben-Weyl, Methoden der organischen Chemie, pub. Georg ThiemeVerlag, Stuttgart), namely, under the reaction conditions which areknown and are suitable for the said reactions.

If desired, the starting materials used for the preparation of thecompounds of general Formula I can be formed in situ in such a mannerthat they are not isolated from the reaction mixture but are immediatelyfurther reacted to give the desired compounds of Formula I.

More particularly, for the preparation of compounds of general Formula Iby cyclization, there can be used compounds of the following generalformulae: ##STR6## wherein R¹ to R⁸, X and E have the values givenabove. The tetrahydroisoquinoline derivatives IIa and IIb are preferablyused for the cyclization.

In general Formulae II, IIa, IIb and IIc, E is a group which iseliminated by the reaction. Therefore, the nature of this substituent isnot critical. E is preferably a chlorine or bromine atom or hydroxy. Ecan also be a fluorine or iodine atom or an esterified hydroxy group,especially a reactively esterified hydroxy group, for example, analkylsulfonyloxy, preferably of up to 6 carbon atoms, such asmethanesulfonyloxy, arylsulfonyloxy, preferably of 6 to 10 carbon atoms,e.g., a benzenesulfonyloxy, p-toluene-sulfonyloxy or 1- or2-naphthalenesulfonyloxy, or acyloxy, especially alkanoyloxy, preferablyof up to 7 carbon atoms, e.g., acetoxy or heptanoyloxy, or benzoyloxy,as well as an ether group which can easily be split off, e.g.,tetrahydropyranyl-2-oxy or, if E is part of an ester (Formula IIb orFormula IIc, if R⁵ is oxygen), can also be alkoxy, preferably of up to 4carbon atoms, more preferably methoxy or ethoxy.

More particularly, E in compounds of general Formula IIa is preferably achlorine, bromine or iodine atom or one of the above-mentioned sulfonicacid ester radicals, preferably a p-toluene-sulfonyloxy. In compounds ofgeneral Formula IIb, E is preferably hydroxy, or alkoxy or acyloxy of upto 4 carbon atoms or a halogen atom. In compounds of general FormulaIIc, E is preferably hydroxy or a halogen atom.

The compounds of general Formula II are cyclized in the presence orabsence of a catalyst and preferably of a basic or acidic catalyst, aswell as in the presence or absence of an additional inert solvent, at atemperature of from about -20° to +300° C.

The choice of the catalysts to be employed depends essentially upon theconstitution of the starting material and of the compound HE to be splitoff. More particularly, as bases there can be used, for example, alkalimetal or alkaline earth metal hydroxides, such as sodium, potassium,barium or calcium hydroxides, alkali metal or alkaline earth metalcarbonates, such as sodium or potassium carbonates, alkali metal oralkaline earth metal bicarbonates, such as sodium or potassiumbicarbonate, alkali metal or alkaline earth metal hydrides, such assodium or potassium hydride, alkali metal or alkaline earth metal amidessuch as sodamide, potassamide or lithium, sodium or potassium piperidideor diisopropylamide, or alkali metal or alkaline earth metalalcoholates, such as sodium or potassium methylate, sodium or potassiumethylate or potassium tert.-butylate, organolkali metal compounds, suchas butyl lithium, phenyl lithium or naphthyl sodium, as well as thealkali metal salts of weak acids, such as sodium acetate, and alsoammonia and primary, secondary and, in particular, tertiary amines, suchas triethylamine, dimethylaniline or pyridine and quanternary bases,such as benzyl trimethyl ammonium hydroxide. As acids, there can beused, for example, hydrohalic acids, such as hydrofluoric, hydrochloricor hydrobromic acid, sulfuric acid, phosphoric acid or polyphosphoricacid, as well as Lewis acids, such as aluminum trichloride, aluminumtribromide, boron trifluoride, zinc chloride, tin tetrachloride, galliumtrichloride or gallium tribromide, and also inorganic acid halides, suchas phosphorus trichloride, phosphorus pentachloride, thionyl chloride orphosphorus oxychloride, or agents splitting off water, for examplecarbodiimides, such as dicyclohexyl carbodiimide. The above-mentionedacids and Lewis acids are especially useful for the cyclization ofcompounds of general Formula IIc, which takes place according to themethods used for Friedel-Crafts alkylation or acylation.

As inert solvents, there can be used, for the cyclization of compoundsof general Formulae IIa and IIb, especially alcohols, such as methanol,ethanol, isopropanol, n-butanol or tert.-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran or dioxan; glycolethers, such as ethylene glycol monomethyl or monoethyl ether (methylglycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme);ketones, such as acetone; amides, such as dimethylformamide orhexamethyl-phosphoric acid triamide; nitriles, such as acetonitrile;nitro compounds, such as nitromethane or nitrobenzene; sulfoxides, suchas dimethyl sulfoxide; carbon disulfide; tertiary bases such aspyridine; chlorinated hydrocarbons, such as methylene chloride,chloroform or trichloroethylene; hydrocarbons, such as petroleum ether,hexane, benzene, toluene or xylenes. There can also be used mixtures ofwater with one of the above-mentioned alcohols, for example, 60%ethanol, as well as mixtures of water with acetone or dioxan. For thecyclization of compounds of general Formula IIc, it is preferred to usethe solvents which are typical for Friedel-Crafts alkylations andacylations, such as petroleum ether, hexane, nitrbenzene or carrbondisulfide. These compounds can also be cyclized by the action oftertiary amines in high boiling alcohols, such as cyclohexanol.

More particularly, the compounds of general Formula IIa are preferablycyclized in the presence of strong bases, such as butyl lithium orpotassium tert.-butylate, in polar solvents, such as tetrahydrofuran,dimethylformamide, hexamethyl phosphoric acid triamide or tert.-butanol,at temperatures of from about -20° C. to +200° C., reaction times offrom about 15 minutes to about 30 hours usually being necessary. Thecyclization of compounds of general Formula IIb takes place especiallyadvantageously, in the absence of a solvent, by heating to temperaturesof from about 140° to 250° C. and preferably of from 170° to 210° C.,whereby it is possible to work at atmospheric pressure or also underreduced pressure. As catalysts for the cyclization of compounds ofgeneral Formula IIc, it is preferred to use hydrofluoric acid oraluminum trichloride, whereby there can be employed either an excess ofthe cyclization agent, such as hydrofluoric acid, as solvent or therecan also be employed one of the above-mentioned additional inertsolvents. Compounds of general Formulla II c are preferably cyclized ata temperature of from about 0° to 150° C. and especially at atemperature of from 20° to 80° C.

It is also possible to cyclize a compound of general Formula II (E = OH)by first reacting it with, for example, thionyl chloride, optionally inthe presence of a base, such as triethylamine or pyridine, to give thecorresponding chloride of general Formula II (E = Cl) which is thenallowed to react furthen in situ to give a compound of general FormulaI.

The hexahydro-pyrazino-isoquinoline derivatives of general Formula I canalso be obtained by reduction of compounds of general Formula III,preferably at a temperature of from about -80° to +250° C., in thepresence of at least one inert solvent.

The compounds of general Formula III correspond to those of generalFormula I except that, in addition, they contain in the IIb(1)- and/or2(3)- and/or 6(7)-position, an additional double bond and/or instead ofthe radical R⁵, in the 7-position there is present an alkylidene groupof up to 4 carbon atoms, preferably a methylene or ethylidene. If anadditional double bond is present in the 2(3)-position, then eitherradical R² is absent from compounds (III) or the compounds (III) arepresent in the form of a quaternary salt. Of the starting materials ofgeneral Formula III, preferred are those with a double bond in theIIb(1)-position.

Catalytic hydrogenation is preferably used for the reduction. Ascatalysts for the hydrogenation, there can be used, for example, a noblemetals or nickel or cobalt catalysts, as well as mixed catalysts, suchas copper-chromium oxide. As noble metals, there are preferably usedplatinum or palladium, which can be present on carriers such ascharcoal, calcium carbonate or strontium carbonate, or as oxides or infinely-divided form. Nickel and cobalt catalysts are preferably employedas Raney metals. It is also possible to use complex compounds of heavymetals as catalysts, for example, soluble rhodium complexes, such ashydridocarbonyl-tris(triphenylphosphine) rhodium. The hydrogenation canbe carried out at pressures of from about 1 to 200 atms. and attemperatures of from anbout -80° to +200° C. and preferably attemperatures of from 20° to 100° C. The reaction can be carried out inan acidic, neutral or basic medium, preferably in the presence of one ofthe inert solvents already mentioned above or also in the presence ofcarboxylic acids, such as acetic acid, or of esters, such as ethylacetate. The hydrogenation is preferably carried out on Raney nickel orwith one of the above-metnioned platinum or palladium catalysts in analcohol, such as methanol or ethanol, at ambient temperature andatmospheric pressure.

If, in the course of the reaction, new asymmetric centers arise, forexample, of the C.sub.(IIb) atom, the reduction can also be directed insuch a manner that one of the two possible antipodes of the compounds ofgeneral Formula I is formed exclusively or at least to a preponderantextent. This can take place, for example, by asymmetric hydrogenation inwhich, as catalysts, there can be used, for example, Raney nickel whichis to be previously treated with an asymmetrical modifying reagent, forexample, with a solution of an optically-active hydroxy or amino acid,such as tartaric acid, citric acid, alanine, isoleucine, lysine,phenylalanine, valine or leucine. As catalyst for an asymmetrichydrogenation in the heterogeneous phase, there can also be used a heavymetal catalyst which is applied to a natural or synthetic polymer, forexample, palladium or platinum on silk or on a specially prepared silicagel or polyamino acid carrier, such as are described in the literature.In homogeneous phase, asymmetric hydrogenation can take place, forexample, with the use of a soluble rhodium complex. The asymmetrichydrogenation is carried out under the abovegiven conditions, preferablyat 1-3 atms. pressure and at a temperature of from about 20° to 50° C.

The compounds of general Formula I can also be obtained from compoundsof general Formula IV by hydroxylation, hydroxlkylation, halogenation ornitration or by treatment with an agent giving off sulfur.

Hydroxylation of compounds of general Formula IV can take place, forexample, in the 1-position by treating the starting material withhydrogen peroxide or with a derivative thereof, such as performic acid,peracetic acid, perbenzoci acid or 3-chloroperbenzoic acid. It ispreferable to hydrogenate in an inert solvent, especially in methylenechloride, chloroform or diethyl ether, at a temperature of from 0° to50° C. and more preferably from 20° to 30° C. The reaction is finishedunder these conditions after about 1 to 48 hours. It proceess especiallywell with starting materialls of general Formula IV in which R¹³ ispyridyl-carbonyl.

A hydroxyalkyl group can be introduced into the 3-position of compoundsof general Formula IV by hydroxyalkylation. Preferred ashydroxyalkylation agent is alkylene oxide or a haloalcohol of up to 4carbon atoms, for example, ethylene oxide or 2-bromoethanol. Thehydroxalkylation is, as a rule, carried out in an inert solvent,preferably in liquid ammonia and/or an ether, such as diethyl ether,tetrahydrofuran or dioxane, a strong base preferably being added ascatalyst, especially sodamide, potassamide or lithamide, lithiumdiisopropylamide or butyl lithium. The reaction temperature is fromabout -80° to +30° C. The reaction is complete in about 1 to 48 hours.

It is also possible by halogenation to introduce one or more halogenatoms, preferably chloride or bromine atoms, into compounds of generalFormula IV. Thus, compounds (IV) can be reacted with elemental chlorineor bromine in an inert solvent, such as diethyl ether, carbontetrachloride or acetic acid, using, as catalysts, for example, ironfilings, iodine, ferric chloride or aluminum chloride. The reactiontemperatures are preferably from about -30° to +100° C. According to themethods described in the literature, the conditions can be so selectedthat the halogenation takes place preferentially in the aromatic nucleusor in the 7-position. In the aromatic nucleus, the 8- and 11-positionsare preferably substituted. It is also possible that severalhalogenation products are formed simultaneously, which can be separated,for example, by chromatograhy or by crystallization. Halogenation isalso possible with other halogenating reagents, for example, with acylhypohalides or N-halo-imides, such as N-chloro o N-bromosuccinimide, inwhich case, as a rule, the reaction is carried out in an inert solventin the given temperature range.

By treatment with nitrating agents, one or more nitro groups can beintroduced into the molecule of the starting compounds of generalFormula IV. Substitution preferably takes place in the 8- or11-position. Preferred as nitrating agent is nitric accid or aderivative thereof, for example, a salt, ester, halide or anhydride(i.e., a nitrogen oxide). The nitration is advantageously carried out inthe presence of an acidic catalyst, for example, sulfuric acid, as wellas hydrofluoric acid or a Friedel-Crafts catalyst, such as borontrifluoride, aluminum trichloride or ferric chloride. An excess of thenitrating agent, for example, of nitric acid and/or an excess of thecatalyst, for example, sulfuric acid, can simultaneously serve assolvent. However, it is also possible to carry out the nitration in thepresence of one or more additional inert solvents. Acetic acid ispreferred. It can also be advantageous to operate in a twophase systemby using a chlorinated hydrocarbon, such as methylene chloride,chloroform or carbon tetrachloride as solvent. As a rule, the nitrationis carried out at a temperature of from -20° to +50° C. and preferablyof from 0° to 20° C.

By treatment of compounds of general Formula IV with an agent giving offsulfur, preferably with phosphorus pentasulfide, the carbonyl groups canbe converted into thiocarbonyl groups. This reaction is preferablycarried out in the presence of an inert solvent, such astetrahydrofuran, dioxane, chloroform, carbon disulfide, benzene, tolueneor a xylene, at a temperature of from about 20° to about 140° C. and iscomplete after about 1 to 12, usually about 2 to 6 hours.

Compounds of general Formula I in which R² is CSR⁹ can be obtained bytreating a compound of general Formula IV, wherein R¹³ is a hydrogenatom, with a thioacylating agent. As thioacylating agent, there can beused, for example, compounds of the general formula R⁹ --CS--E¹ whereinE¹ is a hydroxyl group or O-alkyl, S-alkyl, S--CH₂ COOH, NH₂, NH-alkylor N(alkyl)₂ in which alkyl preferably is of up to 4 carbon atoms. Ofthese thioacylating agents, those of general formulae R⁹ --CS--S--CH₂COOH and R⁹ --CS--NH₂ are preferred. The reaction can take place eitherin the absence of solvent, for example, by heating the reactioncomponents, or in the presence of one or more inert solvents. As inertsolvents, there can be used, for example, water, alcohols, such asmethanol or ethanol, chlorinated hydrocarbons, such as chloroform, orhydrocarbons, such as benzene or toluene. The addition of a base, suchas sodium hydroxide, potassium hydroxide, sodium carbonate, potassiumcarbonate, triethylamine or pyridine, is, as a rule, advantageous. Thethioacylation is normally carried out at a temperature of from about 0°to about 150° C., the higher temperature range being preferred for thereaction with thioamides, for example, those of the general formula R⁹--CS--NH₂. It can also be advantageous to operate under reducedpressure. As a rule, the reaction is complete after about 1 to 24 hours,usually about 6 to 12 hours.

Compounds of general Formula I wherein R² is --CO--R¹¹ can be obtainedby reacting a compound of general Formula IV (R¹³ = H) with a compoundof general formula R¹¹ --CO--E. Of these compounds, chloroformic acidesters of the general formula R¹¹ --CO--Cl are preferred. As a rule, thereaction takes place in the presence of an inert solvent, for example,of a chlorinated hydrocarbon, such as dichloromethane, a basic catalyst,for example, pyridine or triethylamine, preferably being present. Thereaction temperature is from about 0° to about 100° C., preferably from20° to 60° C.

Some of the starting compounds of general formulae II, III and IV areknown. Those that are not known can be prepared according to knownmethods.

For example, isoquinoline derivatives of general Formula IIa can beobtained by hydrogenating an appropriately substituted1-cyano-1,2-dihydro- or 1-cyano-1,2,3,4-tetrahydro-2-R² -isoquinolinesin the presence of Raney nickel at an elevated temperature and pressure,with migration of the R² substituent, to give the corresponding 1-R²-aminomethyl-1,2,3,4-tetrahydroisoquinolines, which can subsequently beconverted with acid chlorides of the general formula E--CHR³ --CX--Clinto compounds of general Formula IIa. If, for example, chloroacetylchloride is used in the last-mentioned stage, then compounds areobtained of general Formula IIa (X = O; R³ = H, E = Cl).

Compounds of general Formula IIb can be obtained, for example, by thereaction of appropriate 1-aminomethyl-1,2,3,4-tetrahydroisoquinolineswith glyoxalic acid and hydrogenation of the Schiff's bases obtained togive the corresponding1-carboxymethylaminomethyl-1,2,3,4-tetrahydroisoquinolines (IIb) (R¹ =R² = R³ = H; X = O; E = OH). By conversion of their carboxyl group,other compounds of general Formula IIb can be obtained in which thesubstituent E has a different value. Compounds of general Formula IIb inwhich R² is a hydrogen atom can also be obtained, for example, byhydrolysis of appropriate 2-Acyl compounds, for example, of2-benzoyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolines.In the course of this hydrolysis, the acetyl and benzoyl group in the2-position can be simultaneously split off and the lactam ring opened.Furthermore, compounds of general Formula IIb can be obtained by variousvariants of the Pictet-Spengler synthesis. Thus, for example,appropriately substituted 2-phenylethylamines can be reacted withderivatives of 2-aminoacetaldehyde, for example, with compounds of thegeneral Formula E--CX--CHR³ --NR² --CHR¹ --CH(O-alkyl)₂, in which thealkyl groups preferably contain up to 4 carbon atoms.

The starting materials of general Formula IIc can be prepared, forexample, by condensing appropriately substituted phenyl-glyoxals withaminomalonic acid diamide to obtain2-aminocarbonyl-3-hydroxy-5-phenylpyrazines. These can be converted byhydrolysis and decarboxylation into 3-hydroxy-5-phenyl-pyrazines fromwhich, by hydrogenation, there are obtained 3-oxo-5-phenyl-piperazines.The reaction thereof with compounds of the general formula R² --Cl andcompounds of the general formula E--CHR⁴ --CR⁵ --E (wherein the two Egroups are preferably different, for example, chloroacetic acid and itsderivatives) or equivalents thereof (for example, alkylene oxides)produces the desired compounds of general Formula IIc.

Starting materials of general Formula III which contain a double bond inthe 11b(1)-position, can be obtained, for example, by theBischler-Napieralski synthesis from appropriately substituted1-(2-phenylethyl)-4-R² -2,6-piperazine-diones. Compounds of generalFormula III with a double bond in the 6(7)-position can be obtained, forexample, from the appropriate 7-oxo compounds by reduction andsubsequent dehydration. The compounds of general Formula III in whichR¹² is an alkylidene group can be obtained from the same 7-oxo compoundsand triphenyl phosphine alkylenes.

Starting materials of general Formula III which contain a double bond inthe 11b(1)-position can be obtained by dehydrogenation of thecorresponding saturated compounds with sulfur, selenium, chloranil orother dehydrogenation agents. The preparation of these startingmaterials is especially of interest when compounds saturated in the11b(1)-position (which are within the scope of compounds of generalFormula I), are present as optically-active antipodes and are lesseffective than one of the other possible antipodes. In this case, theless active antipode can be converted by dehydrogenation into a compound(III) and, by subsequent hydrogenation, converted into the more activesaturated racemate of general Formula I or, by asymmetric hydrogenation,substantially converted into the more active antipodes of generalFormula I.

The starting materials of general Formula IV in which R¹³ is a hydrogenatom or benzoyl, are known. The other compounds of general Formula IVcan be obtained, for example, by acylation of the correspondingcompounds which are unsubstituted in the 2-position.

In a thus-obtained compound of general Formula I, one or more of the R¹to R⁸ and X groups can be converted into a corresponding group havinganother value.

More specifically, it is possible, in a thus-obtained compound ofgeneral Formula I, by treatment with a hydroxylating agent to introducea hydroxy group, with a hydroxyalkylating agent to introduce ahydroxyalkyl radical, with a halogenating agent to introduce one or morehalogen atoms and/or with a nitrating agent to introduce one or morenitro groups and/or by treatment with an agent giving off sulfur, toconvert one or more oxo groups into thioxo groups and/or to convert acompound of general Formula I in which R² is a hydrogen atom, with athioacylating agent into the corresponding thioamide (I) (R² = CS--R⁹)or, by reaction with a compound of the formula R¹¹ --CO--E, into thecorresponding carbonic acid derivative (I) (R² = CO--R¹¹). Theabovedescribed methods are thereby employed but, instead of using acompound of general Formula IV, there is used as starting material anappropriately substituted product of general Formula I.

In a thus-obtained compound of general Formula I, groups which can besplit off by solvolysis, especially acyl radicals, can be split off bytreatment with a solvolyzing agent and/or amino and/or hydroxyl groupscan be acylated by treatment with an acylating agent and/or alkylated bytreatment with an alkylating agent and/or reducible groups present,especially keto, hydroxyl and/or nitro groups and/or halogen atoms, canbe reduced by treatment with a reducing agent or can be replaced byhydrogen and/or carbon-carbon double bonds present can be hydrogenatedand/or amino groups present can be diazotized by treatment with nitrousacid or with a derivative thereof and the diazonium group of thecompounds obtained subsequently replaced by a halogen atom or by ahydroxy, alkoxy, cyano or Z group and/or a hydroxy group converted bytreatment with an inorganic acid halide into a halogen atom and/or aketo group converted by treatment with a fluorination agent into a CF₂group or by reductive amination converted into an amino group.

Solvolytic splitting off of acyl radicals or of thioacyl radicals in the2-position and/or of acyl radicals from the R⁶ or R⁷ groups (when theyare acyloxy, acylamino or benzoyloxy), preferably takes place bytreatment with a solvolyzing agent in an acidic or alkaline medium. Theconditions must thereby be so selected that the lactam group is notsimultaneously split off. Therefore, mild reaction conditions arepreferred. As acids, there can be used for the solvolysis, for example,mineral acids, such as phosphoric acid, sulfuric acid or hydrochloricacid, as well as acid salts, such as potassium hydrogen sulfate. Asbases, there can be used, for example, alkali metal or alkaline earthmetal hydroxides, such as sodium, potassium, calcium or bariumhydroxide, alkali metal carbonates, such as sodium or potassiumcarbonate, alkali metal alcoholates, such as sodium or potassiummethylate or ethylate, as well as, for example, hydrazine hydrate. As arule, the solvolysis is carried out in an aqueous, aqueous-alcoholic oralcoholic medium, for example, in methanol or ethanol. However, it isalso possible to employ an excess of the acid, for example of sulfuricor phosphoric acid, in which case water can also be present. Methanolicor ethanolic hydrochloric acid can also be used as solvolyzing agent.The reaction temperatures for the solvolysis are from about -50° to+200° C. and preferably from about 20° to 150° C. The solvolysis iscomplete after about 0.5 to 72 hours, usually about 2 to 48 hours.

A solvolytic splitting of alkoxy radicals, especially ofaromatically-bound alkoxy radicals, in the compounds obtained of generalFormula I can be carried out with, for example, Lewis acids, such asboron tribromide, in inert solvents, such as methylene chloride orchloroform, at temperatures of from about -40° to +50° C.

Acylation of amino and/or hydroxy groups in a compound obtained ofgeneral Formula I can be carried out with appropriate carboxylic acidsor functional derivatives thereof. For the acylation of an amino groupin the 2-position, there can be used carboxylic acids of the generalformula R⁹ --COOH. For the acylation of hydroxy and/or amino groupswhich are in the aromatic nucleus, there can, on the other hand, be usedfatty acids of up to 4 carbon atoms. Benzoic acid can also be used forO-acylation. As functional derivatives, there are preferably used thecarboxylic acid anhydrides, for example, acetic anhydride, as well asmixed carboxylic acid anhydrides, for example p-fluorobenzoicacid-formic acid anhydride, carboxylic acid halides, preferably thechlorides and bromides, such as acetyl chloride or bromide, and also thecorresponding azides or esters, especially the alkyl esters in whichalkyl preferably is of up to 4 carbon atoms. When carrying out theacylation, an inorganic or organic base is advantageously added, forexample, an alkali metal hydroxide or carbonate, such as sodium orpotassium hydroxide or sodium or potassium carbonate, or a tertiaryamine, such as triethylamine, triisopropylamine or pyridine. As a rule,the reaction is carried out in the presence of an inert solvent, forexample, of an ether, such as diisopropyl ether, tetrahydrofuran ordioxane, of a halogenated hydrocarbon, such as dichloromethane,chloroform, carbon tetrachloride or chlorobenzene, or of a hydrocarbon,such as benzene or toluene. However, as solvent there can also be usedan excess of the carboxylic acid derivative and/or an excess of theadded base. Furthermore, it is possible to produce the actual acylatingagent in situ. For example, the carboxylic acid halides can be producedin situ from the carboxylic acids with the use of halogenating agents,for example, tin tetrachloride, phosphorus trichloride, phosphorustribromide, phosphorus oxychlride, thionyl chloride or phosphoruspentachloride, the reaction thereby being carried out in the presence orabsence of the above-mentioned bases and/or solvents. In carrying outthe acylation, an agent splitting off water can also be added. Forexample, acylation can be carried out with the free carboxylic acid inthe presence of a carbodiimide, such as dicyclohexyl carbodiimide, inone of the above-mentioned solvents. The reaction temperatures for theacylation can be between about 0° and about 200° C. and preferablybetween about 20° and 80° C. The reaction is complete after about 10minutes to 72 hours and usually about 1 to 24 hours.

Acylation can also be carried out with ketenes, preferably in one of theabove-mentioned solvents, with the addition of an acidic catalyst, suchas p-toluene-sulfonic acid or sulfuric acid.

Compounds of general Formula I which contain one or more free hydroxy,amino or monoalkylamino groups as substituents can be aklyated to givethe corresponding alkoxy, monoalkylamino or dialkylamino compounds or togive the corresponding trialkyl ammonium salts.

The alkylation can be carried out according to conventional methods bytreatment with an alkylating agent. For O-alkylation, the startingmaterials are preferably first converted into corresponding salts(phenolates) by the addition of a base, for example of sodium hydroxide,potassium hydroxide or potassium carbonate. As alkylation agents, therecan be used, for example, alkyl halides, such as methyl chloride,bromide or iodide, ethyl chloride, bromide or iodide or thecorresponding dialkyl sulfuric acid or alkyl sulfonic acid esters, forexample dimethyl sulfate, diethyl sulfate or methyl p-toluene-sulfonate.Diazo compounds, such as diazomethane, can also be used for theO-alkylation. Amino compounds can be alkylated with these reagents butalso reductively with aldehydes, such as formaldehyde or acetaldehyde,for example in the presence of hydrogen or formic acid. If the reactionis carried out in the presence of hydrogen, then it is expedient to addone of the catalysts mentioned above for the reduction of compounds ofgeneral Formula III. As solvent, there can be used, for example, waer oraqeuous sodium hydroxide solution, an alcohol, such as methanol, ethanolor n-butanol, an ether, such as tetrahydrofuran or dioxane, an amide,such as dimethylformamide, or a hydrocarbon, such as benzene or axylene. Solvent mixtures can also be employed. The addition of a base,for example of an alkali metal hydroxide, such as sodium or potassiumhydroxide, or of a tertiary amine, such as pyridine or triethylamine,can also be useful.

In the case of the N-alkylation, depending upon the choice of thereaction conditions and of the amount of the added alkylation agent,there can be preponderantly obtained mono- or dialkylamino compounds ortrialkyl ammonium salts. The reaction temperature for the alkylation ispreferably from about -10° to about 150° C. and more preferably fromabout 20° to 100° C.

Furthermore, reducible groups and/or carbon-carbon double bonds presentin the compounds obtained of general Formula I can be reduced bytreatment with a reducing agent or can be replaced by hydrogen.Reducible groups are, in particular, keto and/or hydroxyl groups in the7-position, nitro groups in the 8-, 9-, 10- or 11-position or as acomponent of R⁹, for example as a substituent on a cycloalkyl,cycloalkenyl or phenyl group, halogen atoms in the 7-, 8-, 9-, 10- or11-position or as a component of R⁹ for example, as a substituent on acycloalkyl, cycloalkenyl or phenyl radical. Reducible carbon-carbondouble bonds can occur especially in the radical R⁹ if this is, forexample, a cycloalkenyl group.

These groups and especially carbon-carbon double bonds can be reducedaccording to the above-described methods of catalytic hydrogenation.

Besides the catalytic hydrogenation, other methods of reduction can alsobe employed. However, care must thereby be taken that the lactam orthiolactum group of the ring system is not attacked. However, accordingto the statements in the literature, this is easily possible. Thus, forthe reduction of, for example, keto or nitro groups, reaction withnascent hydrogen can be used, which can be produced, for example, by thetreatment of metals with acids or bases. Thus, for example, there can beused the systems zinc/acid, iron/acid, tin/acid, or zinc/aqueous alkalimetal hydroxide solution. As acids, there can be used, for exaple,hydrochloric acid or acetic acid. Furthermore, as reducing agents, therecan be employed alkali metals, for example sodium, in an alcohol, suchas ethanol, isopropanol or isoamyl alochol; complex metal hydrides,which do not attack the lactam group, such as sodium borohydride,lithium borohydride or potassium trimethoxyborohydride; stannouschloride; or hydrazine. The reduction can be carried out in the presenceof an additional inert solvent, those solvents being employed which areknown from the literature for the individual reduction methods. Thus,for example, complex metal hydrides are used in an ether, such asdiethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane or diglyme,and sodium borohydride also in alcoholic solution, for example, inmethanolic or ethanolic solution, or in aqueous alcoholic or aqueoussolution. In general, the reduction reaction is carried out at atemperature of from about -80° to +250° C. and preferably of from -20°to +100° C.

Keto groups and especially keto groups in the 7-position can beconverted into methylene groups by catalytic hydrogenation on palladiumcatalysts or by reaction with hydrazine and subsequent thermaldecomposition of the hydrazone formed, by the Wolff-Kishner method. Thelast-mentioned reaction is preferably carried out in the presence of astrong base and of a high boiling solvent, such as diethylene glycol.

In a compound obtained of general Formula I which contains one or morearomatically bound amino groups, these groups can be converted bydiazotization into the corresponding diazonium compounds. Diazotizationcan be carried out, for example, in acidic aqueous solution, for examplein the presence of sulfuric acid, hydrochloric acid, hydrobromic acid ortetrafluoroboric acid, by the addition of an inorganic nitrite,preferably of sodium or potassium nitrite, at a temperature of fromabout -20° to +10° C. It is also possible to use an organic nitrite, forexample, n-butyl nitrite, n-amyl nitrite or isoamyl nitrite, at atemperature of from about -20° to +10° C. in an inert solvent, such asdiethyl ether, tetrahydrofuran or dioxane.

The diazonium group in the diazonium compounds thus obtained can beexchanged, for example, for fluorine, chlorine, bromine, iodine,hydroxyl, alkoxy, cyano or Z groups.

For the introduction of a fluorine atom, diazotization is carried out,for example, with anhydrous hydrofluoric acid and then subsequentlyheated or the diazonium salt is reacted with tetrafluoroboric acid togive the sparingly-soluble diazonium tetrafluoroborates. These can beisolated and thermally converted into the desired fluoro compounds, forexample by heating in an inert solvent. The diazonium tetrafluoroboratescan also, without isolation, be decomposed in aqueous suspension byirradiation with a mercury lamp. The diazonium group can be exchangedfor chlorine or bromine, preferably in hot solution, in the presence ofcuprous chloride or cuprous bromide, by Sandmeyer's method. The exchangeof a diazonium iodide group for iodine even takes place by slightheating, whereby there can also be added catalysts, such as cuprousiodide, bromide or chloride. Hydrolysis of the diazonium salts,preferably with heating, leads to the corresponding hydroxy compounds.The diazonium salt grouping can also be exchanged for an alkoxy radical,for example, by heating in an aqeuous-alcoholic solution. Thereplacement of the diazonium group for a cyano group can be carried out,for example, by Sandmeyer's method in the presence of cuprous cyanideand an alkali metal cyanide, such as sodium or potassium cyanide, evenin the cold, for example, at a temperature of from about 0° to +50° C.

The diazonium compounds can also be coupled with approprite couplingcomponents to give azo dyestuffs of the general Formula I, in which R⁶or R⁷ are Z and/or R⁹ is a Z-substituted phenyl radical. These compoundshave, compared to the basic amino compounds, the advantage of being morestable and of being easier to incorporate into pharmaceuticalformulations. As coupling components, most preferred are benzene andnaphthalene derivatives which can easily be coupled, for example, thosewhich carry in the p-position activating substituents, such as amino,alkylamino, dialkylamino, hydroxy or alkoxy groups, and, in addition,can also contain further substituents, such as carboxy, halogen,preferably fluorine or chlorine, sulfo or alkyl.

It is also possible to convert a hydroxy group present in the productobtained of general Formula I, especially an aliphatically-bound hydroxygroup, by treatment with an inorganic acid halide, such as thionylchloride, phosphorus trichloride, phosphorus tribromide, or phosphoruspentachloride, into a halogen atom. It is preferable to work in thepresence of an inert solvent, such as dichloromethane, chloroform orcarbon tetrachloride, at a temperature of from about 20° to about 80° C.

It is also possible to convert a keto group in R⁹ into a CF₂ group, forexample, with sulfur tetrafluoride or phenyl sulfur trifluoride, in thepresence of hydrogen fluoride or also with carbonyl difluoride in thepresence of pyridine. In these reactions, it is preferable to employinert solvents, such as methylene chloride, chloroform ortetrahydrofuran. The reaction temperature can be from about 0° to 150°C. and is preferably from about 20° to 50° C. It can also beadvantageous to operate under pressure.

When a keto group is present in R⁹, it can be converted by reductiveamination in one or more stages into an amino group. Thus, for example,it is possible to convert a keto group with hydroxylamine into an oximeor with hydrazine into a hydrazone and catalytically to hydrogenate thederivatives thus-obtained, for example, on Raney nickel, at 1 to 50 andpreferably at about 5 to 10 atms. pressure. It is also possible tohydrogenate the ketone in the presence of ammonia or of a monoalkylamineor dialkylamine, preferably at a pressure of from about 1 to 200 andespecially of from 80 to 120 atms. pressure. As solvents for thelast-mentioned form of amination, there can be used, for example,alcohols, such as methanol, ethanol or isopropanol, as well as ethers,such as tetrahydrofuran or dioxane. Liquid ammonia can also be employed.The reaction temperatures can be from about -40° to +150° C., preferablyabout 60° to 80° C. The reaction times are about 4 to 24 hours,preferably about 8 to 12 hours.

A free base of general Formula I can be converted in a conventionalmanner with an acid into an acid addition salt thereof. For thisreaction, those acids can be used which give physiologically acceptablesalts. Thus, inorganic acids can be used, for example, sulfuric acid,nitric acid, hydrohalic acids, such as hydrochloric acid, hydrobromicacid or hydriodic acid, phosphoric acids, such as orthophosphoric acid,or sulfamic acid; and organic acids, especially aliphatic, alicyclic,araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic orsulfonic acids, such as formic acid, acetic acid, propionic acid,butyric acid, pivalic acid, diethylacetic acid, oxalic acid, malonicacid, succinic acid, pimelic acid, fumaric acid, maleic acid, lacticacid, tartaric acid, malic acid, gluconic acid, citric acid, benzoicacid, salicylic acid, phenylpropionic acid, ascorbic acid, nicotinicacid, isonicotinic acid, methane- and ethane-sulfonic acid,ethane-disulfonic acid, 2-hydroxyethane-sulfonic acid, benzene-sulfonicacid, p-toluene-sulfonic acid, naphthalene-mono- or disulfonic acids,for example naphthalene1- or -2-sulfonic acid or naphthalene-1,5- or-2,6-disulfonic acid, can be used.

Acidic compounds of general Formula I and especially those which containa phenolic hydroxyl group and/or a carboxyl group and/or a sulfo group,can, by treatment with a base, be converted into the correspondingphysiologically compatible metallic or ammonium salts. Preferred saltsinclude the sodium, potassium, calcium, ammonium and substitutedammonium salts, for example, the cyclohexyl, benzyl or triethanolammonium salts.

Compounds of general Formula I which carry a primary, secondary ortertiary amino group, can, by treatment with a quaternizing alkylationagent, such as a methyl or ethyl halide or dimethyl sulfate, andpreferably with an excess of such an alkylation agent, be converted intotheir physiologically compatible quaternary ammonium salts.

The free bases of general Formula I can, if desired, be liberated fromtheir salts by tratment with strong bases, such as sodium or potassiumhydroxide or sodium or potassium carbonate. Analogously, the acidiccompounds of general Formula I can be liberated from their metallic orammonium salts by treatment with a strong acid, such as hydrochloricacid or sulfuric acid.

In some of the above-described reactions, products are obtained ofindefinite constitution. For example by halogenation or nitration ofcompounds of general Formula IV or of compounds of general Formula I,wherein R⁶ and R⁷ are hydrogen atoms, products are formed in which theposition of the newly introduced substituents is not known. The positionof the substituents is, in the case of such compounds, indicated in thefollowing with a question mark or an alternative statement, i.e.,"-8(?)-bromo" means, for example, that in the product in question, thebromine atom is presumably but not proven to be in the 8-position.Similarly, "8-(or 11)-nitro," for example, means that in the compound inquestion, the nitro group is, in all probability, in the 8- or11-position but that the exact position of the nitro group has notdefinitely been established.

The compounds of general Formula I possess at least one center ofasymmetry in the 11b-position. In the case of appropriate substitution,they can possess further centers of asymmetry. Therefore, in the case oftheir syntheses, they can be obtained as racemates or, ifoptically-active starting materials have been used, can also be obtainedin optically-active form. If the compounds have two or more centers ofasymmetry, then they are generally obtained from the syntheses in theform of mixtures of racemates from which the individual racemates can beisolated in pure form, for example by recrystallization or bychromatography. However, it is also possible that only one of thepossible racemates is preponderantly or exclusively obtained. This isespecially the case when starting from a sterically uniform startingmaterial. In this connection, those compounds of general Formula I areto be particularly mentioned in which R⁴ is other than hydrogen, i.e.,alkyl or phenyl and especially methyl. These compounds are, in thefollowing, called cis compounds when the hydrogen atom in the 6- and11b-position is in the cis position, for example, 6-cis-methyl.Otherwise, they are called trans compounds. The stereochemicalassignment has taken place with great probability but not with absolutecertainty.

Racemates obtained can, if desired, be mechanically or chemicallyseparated into their optical antipodes by known methods. From theracemates there are preferably formed diastereomers by reaction withoptically-active separating agents. For example, a racemate of generalFormula I which contains a basic group, for example, an amino group, canbe converted with an optically-active acid into the corresponding salt.As acids for this purpose, there can be used, for example, dextro- andlaevo-rotary antipodes of tartaric acid, dibenzoyltartaric acid,diacetyltartaric acid, camphoric acid, camphor-sulfonic acids, mandelicacid, malic acid, lactic acid, 2-phenylbutyric acid, dinitrodiphenicacid or quinic acid. Racemates of general Formula I which contain anacidic group, for example a carboxylic acid or sulfonic group, can bereacted analogously with an optically-active base, for example, withstrychnine, brucine, quinine or one of the optically-active forms of1-phenylethylamine. The diastereomeric mixtures obtained cansubsequently be separated by crystallization or by manual selection. Thedesired optically-active antipodes of the compounds of general Formula Ican subsequently be obtained by hydrolytic decomposition of the isolateddiastereomeric salts.

The compounds of general Formula I and their physiologically acceptablesalts have an excellent activity against cestodes and trematodes. Theycan, for example, be used against the following cestodes (arrangedaccording to host):

1. Ruminants: Moniezia, Stilesia, Avitellina, Thysanosoma, Thysaniezia,hydatids of Taneia sp., Coenurus cerebralis, Echinococci hydatids;

2. Ungulates: Anoplocephala;

3. Rodents: Hymenolepis (especially H. nana and H.diminuta);

4. Birds: Davainea, Raillietina, Hymenolepis;

5. Canines and felines: Taenia (especially T. hydatigena, T. pisiformis,T. taeniaeformis, T. ovis, T. serialis, T. cervi, T. multiceps),Dipylidium (especially D. caninum), Echinococcus (especially E.granulosus and E. multilocularis);

6. Humans: Taenia (especially T. solium, T, saginata, T. serialis),Hymenolepis (especially H. nana and H. diminuta), Drepanidotaenia,Dipylidium, Diplopylidium, Coenurus (especially C. cerebralis,Diphyllobothrium (especially D. latum), Echinococcus hydatids(especially E. granulosis and E. multilocularis).

The trematodes which are important to combat in human and veterinarymedicine include those of the families Schistosomidae, especially of thegenus Schistosoma (Sch. mansoni, Sch. haemotobium and Sch. japonicum).The genuses Fasciola, Dicrocoelium, Clonorchis, Opisthorchis,Paragonimus, Paramphistomum, Echinostoma and the like can possible alsobe influenced.

The compounds of general Formula I and their physiologically acceptablesalts can be used, inter alia, in the following host and/or intermediatehost organisms for combating cestodes or trematodes and/or their larvae:humans, various species of monkeys, as well as the most importantdomestic and wild animals, for example, the various canines, such asdogs and foxes; felines, such as cats; ungulates, such as horses,donkeys and mules; cervids, such as roe, red and fallow deer, chamois;rodents; ruminants, such as cows, sheep and goats; birds, such as hensand ducks; pigs; fish and the like.

Habitats of susceptible parasites or of their larvae include, inparticular, the gastro-intestinal tract, for example, the stomach,intestines, pancreas and bile duct. However, various other organsinclude, for example, liver, kidneys, heart, spleen, lymph nodes, brain,spinal cord and testes, the abdominal cavity, connective tissue,musculature, peritoneum, pleura, diaphragm, lungs, and blood vessels;thus, the compounds of general Formula I are active, with goodcompatibility, for example, against Schistosoma sp. in the bloodvessels, against Hymenolepis microstoma in the bile duct and against T.hydatigena hydatids in the liver.

The compounds of general Formula I and their physiologically acceptablesalts can be used as such or in combination with pharmaceuticallyacceptable, inert carriers. Carriers of this type can include, forexample, capsules, solid diluents or filler materials, sterile aqeuousmedia and/or various non-toxic organic solvents.

Forms of administration which can be used include, for example, tabletsand dragees (which can also contain the active material in depot form),effervescent tablets, capsules, granulates, aqueous suspensions,injectable solutions, emulsions and suspensions, elixirs, syrups orpastes. The formulations for this purpose can be prepared in knownmanner, for example, by the addition of the active materials to solventsand/or carrier materials, optionally with the use of emulsifying agentsand/or dispersion agents. As adjuvants, there can be used, for example,water, non-toxic organic solvents (e.g., paraffins or alcohols, such asglycerol or polyethylene glycol), vegetable oils (e.g., sesame oil),solid carrier materials, such as natural or synthetic mineral powders(e.g., talc or highly dispersed silicic acid), sugars, emulsifiers(e.g., ionic or non-ionic), dispersion agents (e.g., methyl-cellulose ofpolyvinyl-pyrrolidone) and/or lubricants (e.g., magnesium stearate).Tablets can also contain additives, such as sweetening agents, sodiumcitrate, calcium carbonate and dicalcium phosphate, together with otheradditives, such as starch, gelatine and the like. Aqueous suspensionsand/or elixirs can, if desired, contain flavor improvers and/or coloringmaterials. The active compounds can, if desired, also be administeredwithout or almost without adjuvants, for example in capsules.

The active compounds are preferably administered orally but parenteral,especially subcutaneous or intramuscular, as well as dermaladministration is also possible.

For combatting adult cestodes, it is advantageous to administer theactive materials one or more times daily in amounts of from 0.01 to 250mg/kg. and preferably of from about 0.5 to 100 mg/kg., orally orsubcutaneously. For combatting the corresponding tapeworm larvae(hydatids) or Schistosoma, larger amounts of active material may benecessary.

When administering comparatively large amounts of active material, theycan also be divided over the course of the day into smaller individualdosages. Thus, instead of a single 1000 mg. dose, five separate dosages,each of 200 mg., can be administered. In veterinary medicine,administration with the animal feed can also be used, in which case itis preferable first to prepare an appropriate pre-mix containing theactive material. Here again, all conventional additive materials canalso be used.

If necessary, it is possible to deviate from the abovementioned amounts,depending upon the body weight or the nature of the route of applicationbut also on the basis of species and of the individual behavior thereoftowards the medicament or the nature of its formulation or the point oftime or interval at which administration takes place. Thus, in somecases, it can suffice to administer less than the abovementioned minimumamount, whereas, in other cases, it is necessary to exceed the upperlimit.

Depending upon the nature of the administration, the ratio between theactive compounds and the carrier and/or adjuvant employed can vary veryconsiderably. If, for example, an active compound is administered as atablet or dragee, then about 0.01 to 2500 mg. of active material can becombined with about 1 to 10,000 mg. of adjuvant. If, on the other hand,an active compound is formulated as a premix for a medicated feed, thenfor each 1 kg. of carrier or adjuvant material, there can be used about0.1 to 400 g. of active compound. When formulated as an injectionliquid, a solution of 1 liter of liquid can contain, depending upon thenature of the solubilizing agent, about 0.5 to 100 g. of activecompound. Similarly, 1 liter of syrup can contain dissolved or suspendedtherein about 0.5 to 250 g. of active compound.

The active compounds can also be present in the formulations inadmixture with other active materials. Thus, to achieve a broaderspectrum of activity, it is sometimes useful to add a material activeagainst nematodes, for example, thiabendazole[2-(4-thiazolyl)-benzimidazole] or piperazine (or piperazinederivatives, such as N-methylpiperazine). It is also possible toadminister a mixture of two or more compounds of general Formula Iand/or their physiologically acceptable salts.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the following examples, the "usual working up" means the followingprocedure: if necessary, there is added water and/or organic extractionagent, such as dichloromethane, chloroform or an ether, followed byseparation, washing the organic phase with dilute hydrochloric acid(provided that the product is not basic) and with water, separation,drying over anhydrous magnesium or sodium sulfate, evaporation andpurification of the crude product by crystallization and/orchromatography. The infra-red spectra are measured in potassium bromide.The abbreviation "HPI" employed in the following examples means"1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline."

EXAMPLE 1

a. 300 ml. of a 20% n-butyl lithium solution in hexane are added, underan atmosphere of nitrogen, at 5° - 10° C. and with vigorous stirring tob 216 g.N-(2-chloroacetyl-3-cis-methyl-1,2,3,4-tetrahydroisoquinolyl-1-methyl)-benzamide(m.p. 140° C.; obtainable fromN-(3-cis-methyl-1,2,3,4-tetrahydroisoquinolyl-1-methyl)-benzamide byreaction with chloroacetyl chloride) in 4 liters anhydroustetrahydrofuran. The reaction mixture is stirred for 2 hours at 20° C.,then hydrolyzed with water, whereafter the solvent is evaporated off andthe residue worked up as usual to give 2-benzoyl-4-oxo-6-cis-methyl-HPIwhich, after recrystallization from methanol, melts at 165° C.

The following compounds are obtained in an analogous manner by cyclizingthe appropriate isoquinoline derivatives:

2-acetyl-4-oxo-6-cis-methyl-HPI

2-propionyl-4-oxo-6-cis-methyl-HPI

2-butyryl-4-oxo-6-cis-methyl-HPI

2-isobutyryl-4-oxo-6-cis-methyl-HPI; m.p. 136° C.

1-methyl-2-isobutyryl-4-oxo-HPI

2-isobutyryl-3-methyl-4-oxo-HPI

2-isobutyryl-4-oxo-6-cis-methyl-HPI

2-isobutyryl-4-oxo-6-trans-methyl-HPI

2-isobutyryl-4-oxo-7-methyl-HPI

2-isobutyryl-4-oxo-8-methyl-HPI

2-isobutyryl-4-oxo-9-methyl-HPI

2-isobutyryl-4-oxo-b 10-methyl-HPI

2-isobutyryl-4-oxo-11-methyl-HPI

2-isobutyryl-4-oxo-11b-methyl-HPI

2-valeryl-4-oxo-6-cis-methyl-HPI

2-trimethylacetyl-4-oxo-6-cis-methyl-HPI

2-capronyl-4-oxo-6-cis-methyl-HPI

2-oenanthoyl-4-oxo-6-cis-methyl-HPI

1-methyl-2-cyclohexylcarbonyl-4-oxo-HPI

1-n-butyl-2-cyclohexylcarbonyl-4-oxo-HPI

2-cyclohexylcarbonyl-3-methyl-4-oxo-HPI

2-cyclohexylcarbonyl-3-ethyl-4-oxo-HPI

2-cyclohexylcarbonyl-3-n-butyl-4-oxo-HPI

2-cyclohexylcarbonyl-4-oxo-6-cis-methyl-HPI

2-cyclohexylcarbonyl-4-oxo-6-trans-methyl-HPI; m.p. 134° C.

2-cyclohexylcarbonyl-4-oxo-5-cis-ethyl-HPI

2-cyclohexylcarbonyl-4-oxo-6-trans-ethyl-HPI

2-cyclohexylcarbonyl-4-oxo-6-cis-isopropyl-HPI

2-cyclohexylcarbonyl-4-oxo-6-trans-isopropyl-HPI

2-cyclohexylcarbonyl-4-oxo-6-cis-phenyl-HPI

2-cyclohexylcarbonyl-4-oxo-6-trans-phenyl-HPI

2-cyclohexylcarbonyl-4-oxo-7-methyl-HPI

2-cyclohexylcarbonyl-4-oxo-7-ethyl-HPI

2-cyclohexylcarbonyl-4-oxo-7-phenyl-HPI

2-cyclohexylcarbonyl-4-oxo-8-methyl-HPI

2-cyclohexylcarbonyl-4-oxo-8-ethyl-HPI

2-cyclohexylcarbonyl-4-oxo-9-methyl-HPI

2-cyclohexylcarbonyl-4-oxo-9-ethyl-HPI

2-cyclohexylcarbonyl-4-oxo-10-methyl-HPI

2-cyclohexylcarbonyl-4-oxo-10-ethyl-HPI

2-cyclohexylcarbonyl-4-oxo-11-methyl-HPI

2-cyclohexylcarbonyl-4-oxo-11-ethyl-HPI

2-cyclohexylcarbonyl-4-oxo-11b-methyl-HPI; m.p. 143° C.

2-cyclohexylcarbonyl-4-oxo-11b-ethyl-HPI

2-cyclohexylcarbonyl-4-oxo-11b-n-butyl-HPI

2-cyclohexylcarbonyl-4-oxo-9,10-dimethoxy-HPI

1-methyl-2-(4-oxo-cyclohexylcarbonyl)-4-oxo-HPI

2-(4-oxo-cyclohexylcarbonyl)-3-methyl-4-oxo-HPI

2-(4-oxo-cyclohexylcarbonyl)-4-oxo-6-cis-methyl-HPI

2-(4-oxo-cyclohexylcarbonyl)-4-oxo-6-trans-methyl-HPI; m.p.118° - 120°C.

2-(4-oxo-cyclohexylcarbonyl)-4-oxo-7-methyl-HPI

2-(4-oxo-cyclohexylcarbonyl)-4-oxo-8-methyl-HPI

2-(4-oxo-cyclohexylcarbonyl)-4-oxo-9-methyl-HPI

2-(4-oxo-cyclohexylcarbonyl)-4-oxo-10-methyl-HPI

2-(4-oxo-cyclohexylcarbonyl)-4-oxo-11-methyl-HPI

2-(4-oxo-cyclohexylcarbonyl)-4-oxo-11b-methyl-HPI

1-methyl-2-(tetrahydropyranyl-4-carbonyl)-4-oxo-HPI

2-(tetrahydropyranyl-4-carbonyl)-3-methyl-4-oxo-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-6-cis-methyl-HPI; m.p. 156° -159° C.

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-6-trans-methyl-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-7-methyl-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-8-methyl-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-9-methyl-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-10-methyl-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-11-methyl-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-11b-methyl-HPI

1-methyl-2-(thiacyclohexyl-4-carbonyl)-4-oxo-HPI

2-(thiacyclohexyl-4-carbonyl)-3-methyl-4-oxo-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-6-cis-methyl-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-6-trans-methyl-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-7-methyl-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-8-methyl-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-9-methyl-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-10-methyl-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-11-methyl-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-11b-methyl-HPI

1-methyl-2-benzoyl-4-oxo-HPI

2-benzoyl-3-methyl-4-oxo-HPI; m.p. 176° C.

2-benzoyl-3-ethyl-4-oxo-HPI

2-benzoyl-3-n-propyl-4-oxo-HPI

2-benzoyl-3-isopropyl-4-oxo-HPI

2-benzoyl-3-n-butyl-4-oxo-HPI

2-benzoyl-4-oxo-6-trans-methyl-HPI; m.p. 195° C.

2-benzoyl-4-oxo-6-cis-ethyl-HPI

2-benzoyl-4-oxo-6-trans-ethyl-HPI

2-benzoyl-4-oxo-6-cis-n-propyl-HPI

2-benzoyl-4-oxo-6-trans-n-propyl-HPI

2-benzoyl-4-oxo-6-cis-isopropyl-HPI

2-benzoyl-4-oxo-6-trans-isopropyl-HPI

2-benzoyl-4-oxo-6-cis-n-butyl-HPI

2-benzoyl-4-oxo-6-trans-n-butyl-HPI

2-benzoyl-4-oxo-6-cis-isobutyl-HPI

2-benzoyl-4-oxo-6-trans-isobutyl-HPI

2-benzoyl-4-oxo-6-cis-sec.-butyl-HPI

2-benzoyl-4-oxo-6-trans-sec.-butyl-HPI

2-benzoyl-4-oxo-6-cis-tert.-butyl-HPI

2-benzoyl-4-oxo-6-trans-tert.-butyl-HPI

2-benzoyl-4-oxo-6-cis-phenyl-HPI

2-benzoyl-4-oxo-6-trans-phenyl-HPI

2-benzoyl-4-oxo-7-methyl-HPI; m.p. 157° C.

2-benzoyl-4-oxo-7-ethyl-HPI

2-benzoyl-4-oxo-7-n-propyl-HPI

2-benzoyl-4-oxo-7-isopropyl-HPI

2-benzoyl-4-oxo-7-n-butyl-HPI

2-benzoyl-4-oxo-7-isobutyl-HPI

2-benzoyl-4-oxo-7-sec.-butyl-HPI

2-benzoyl-4-oxo-7-tert.-butyl-HPI

2-benzoyl-4-oxo-8-methyl-HPI

2-benzoyl-4-oxo-8-ethyl-HPI

2-benzoyl-4-oxo-9 -methyl-HPI; m.p. 162° - 163° C.

2-benzoyl-4-oxo-9-ethyl-HPI

2-benzoyl-4-oxo-10-methyl-HPI

2-benzoyl-4-oxo-10-ethyl-HPI

2-benzoyl-4-oxo-11-methyl-HPI

2-benzoyl-4-oxo-11-ethyl-HPI

2-benzoyl-4-oxo-11b-methyl-HPI

2-benzoyl-4-oxo-11b-ethyl-HPI

2-benzoyl-4-oxo-9,10-dimethoxy-HPI; m.p. 130° C.

2-benzoyl-4-oxo-9,10-diethoxy-HPI

2-benzoyl-4-oxo-9,10-diacetoxy-HPI

2-benzoyl-4-oxo-9,10-dibenzoyloxy-HPI

1-methyl-2-(3-fluorobenzoyl)-4-oxo-HPI

2-(3-fluorobenzoyl)-3-methyl-4-oxo-HPI

2-(3-fluorobenzoyl)-4-oxo-6-cis-methyl-HPI

2-(3-fluorobenzoyl)-4-oxo-6-trans-methyl-HPI

2-(3-fluorobenzoyl)-4-oxo-7-methyl-HPI

2-(3-fluorobenzoyl)-4-oxo-8-methyl-HPI

2-(3-fluorobenzoyl)-4-oxo-9-methyl-HPI

2-(3-fluorobenzoyl)-4-oxo-10-methyl-HPI

2-(3-fluorobenzoyl)-4-oxo-11-methyl-HPI

2-(3-fluorobenzoyl)-4-oxo-11b-methyl-HPI

1-methyl-2-(4-fluorobenzoyl)-4-oxo-HPI

2-(4-fluorobenzoyl)-3-methyl-4-oxo-HPI

2-(4-fluorobenzoyl)-4-oxo-6-cis-methyl-HPI

2-(4-fluorobenzoyl)-4-oxo-6-trans-methyl-HPI; m.p. 158° C.

2-(4-fluorobenzoyl)-4-oxo-7-methyl-HPI

2-(4-fluorobenzoyl)-4-oxo-8-methyl-HPI

2-(4-fluorobenzoyl)-4-oxo-9-methyl-HPI

2-(4-fluorobenzoyl)-4-oxo-10-methyl-HPI

2-(4-fluorobenzoyl)-4-oxo-11-methyl-HPI

2-(4-fluorobenzoyl)-4-oxo-11b-methyl-HPI

b. 15 g. boron tribromide are added dropwise at 5° - 10° C. to 6 g.2-benzoyl-4-oxo-9,10-dimethoxy-HPI in 100 ml. dichloromethane,whereafter the reaction mixture is stirred for an hour at 20° C. andthen poured onto ice. The crystals which separate out are washed withwater, dissolved in 200 ml. hot methanol and mixed with 50 ml. 12.5%hydrochloric acid. After an hour, the reaction mixture is evaporated andworked up as usual. There is obtained 2-benzoyl-4-oxo-9,10-dihydroxy-HPIwhich, after recrystallization from methanol, melts at 140° C.

c. 5.5 g. 2-benzoyl-4-oxo-9,10-dibenzoyloxy-HPI are stirred in 200 ml.10% aqueous sodium hydroxide solution for 12 hours at 20° C., insolublematerial is then filtered off and the filtrate is then acidified withhydrochloric acid and worked up as usual to give2-benzoyl-4-oxo-9,10-dihydroxy-HPI, which melts at 140° C.

d. 3.4 g. 2-benzoyl-4-oxo-9,10-dihydroxy-HPI in 100 ml. methanol aremixed with an excess of ethereal diazomethane solution until a paleyellow coloration remains, whereafter the reaction mixture is evaporatedto give 2-benzoyl-4-oxo-9,10-dimethoxy-HPI which, afterrecrystallization from ethanol/ether, melts at 130° C.

e. 1.15 g. sodium borohydride is added portionwise at 0° C. to 6.8 g.2-(4-oxo-cyclohexylcarbonyl)-4-oxo-6cis-methyl-HPI in 100 ml. ethanol,whereafter the reaction mixture is stirred for 12 hours at 20° C. andthen poured on to ice. There is thus obtained2-(4-hydroxycyclohexylcarbonyl)-4-oxo-6-cis-methyl-HPI in the form of anamorphous isomeric mixture.

f. 6.8 g. 2-(4-oxo-cyclohexylcarbonyl)-4-oxo-6trans-methyl-HPI in 100ml. methanol are hydrogenated in the presence of 2 g. Raney nickel for 2hours at 50° C. and 100 atms. pressure and then filtered and thefiltrate is evaporated to give2-(4-hydroxycyclohexylcarbonyl)-4-oxo6-trans-methyl-HPI in the form ofan amorphous isomeric mixture.

g. 3.4 g. 2-(4-oxo-cyclohexylcarbonyl)-4-oxo-6trans-methyl-HPI, 0.2 ml.water, 3.2 g. sulfur tetrafluoride and 50 ml. dichloromethane are shakenin an autoclave for 24 hours at 30° C., whereafter the reaction mixtureis poured into a dilute aqueous solution of sodium carbonate and workedup as usual to give2-(4,4-difluorocyclohexylcarbonyl)-4-oxo-6-trans-methyl-HPI.

h. 135 g. 2-benzoyl-4-oxo-6-cis-methyl-HPI are boiled in 1.5 liters 25%hydrochloric acid and 100 ml. methanol for 12 hours, whereafter thereaction mixture is cooled, the benzoic acid which separates out isfiltered off and the filtrate is washed with diethyl ether. The crudeproduct obtained after working up in the usual way is heated for 2 hoursat 16 mm.Hg. at 200° C. and the reaction mixture, after cooling, isdissolved in water and washed with ether. The aqueous phase is reducedalkaline, extracted with chloroform and worked up as usual. There isobtained 4-oxo-6-cis-methyl-HPI which, after recrystallization frombenzene/petroleum ether, melts at 119° - 120° C.

EXAMPLE 2

a.1-carboxymethylaminomethyl-3-cis-methyl-1,2,3,4-tetrahydroisoquinolinehydrochloride (obtained by the reaction of1-aminomethyl-3-cis-methyl-1,2,3,4-tetrahydroisoquinolinemonohydrochloride with chloroacetic acid in dimethylformamide) is heatedfor 2 hours at 12 mm.Hg. at 195° C., then cooled, dissolved in water,washed with ether and rendered alkaline. After extraction withchloroform and the usual working up, there is obtained4-oxo-6-cismethyl-HPI, which melts at 119 - 120° C.

The following compounds are obtained analogously by ring closure of theappropriate tetrahydroisoquinolines:

1-methyl-4-oxo-HPI

1-ethyl-4-oxo-HPI

3-methyl-4-oxo-HPI

3-ethyl-4-oxo-HPI

3-n-propyl-4-oxo-HPI

3-isopropyl-4-oxo-HPI

3-n-butyl-4-oxo-HPI

3-isobutyl-4-oxo-HPI

3-tert-butyl-4-oxo-HPI

4-oxo-6-trans-methyl-HPI; m.p. 135° - 136° C.

4-oxo-6-cis-ethyl-HPI

4-oxo-6-trans-ethyl-HPI

4-oxo-6-cis-n-propyl-HPI

4-oxo-6-trans-n-propyl-HPI

4-oxo-6-isopropyl-HPI

4-oxo-6-trans-isopropyl-HPI

4-oxo-6-cis-n-butyl-HPI

4-oxo-6-trans-n-butyl-HPI

4-oxo-6-cis-isobutyl-HPI

4-oxo-6-trans-isobutyl-HPI

4-oxo-6-cis-sec.-butyl-HPI

4-oxo-6-trans-sec.-butyl-HPI

4-oxo-6-cis-tert.-butyl-HPI

4-oxo-6-trans-tert.-butyl-HPI

4-oxo-7-methyl-HPI

4-oxo-7-ethyl-HPI

4-oxo-8-methyl-HPI

4-oxo-8-n-butyl-HPI

4-oxo-8-hydroxy-HPI

4-oxo-8-methoxy-HPI

4-oxo-8-amino-HPI

4-oxo-8-methylamino-HPI

4-oxo-8-dimethylamino-HPI

4-oxo-8-nitro-HPI

4-oxo-8-fluoro-HPI

4-oxo-8-chloro-HPI

4-oxo-9-methyl-HPI

4-oxo-9-hydroxy-HPI

4-oxo-9-methoxy-HPI

4-oxo-9-amino-HPI

4-oxo-9-methylamino-HPI

4-oxo-9-dimethylamino-HPI

4-oxo-9-nitro-HPI

4-oxo-9-fluoro-HPI 4-oxo-9-chloro-HPI

4-oxo-10-methyl-HPI

4-oxo-10-hydroxy-HPI

4-oxo-10-methoxy-HPI

4-oxo-10-amino-HPI

4-oxo-10-methylamino-HPI

4-oxo-10-dimethylamino-HPI

4-oxo-10-nitro-HPI

4-oxo-10-fluoro-HPI

4-oxo-10-chloro-HPI

4-oxo-11-methyl-HPI

4-oxo-11-hydroxy-HPI

4-oxo-11-methoxy-HPI

4-oxo-11-amino-HPI

4-oxo-11-methylamino-HPI

4-oxo-11-dimethylamino-HPI

4-oxo-11-nitro-HPI

4-oxo-11-fluoro-HPI

4-oxo-11-chloro-HPI

4-oxo-11b-methyl-HPI

4-oxo-11b-ethyl-HPI

b. 5.5 g. 4-nitrobenzoyl chloride in 100 ml. chloroform are added to 5g. 4-oxo-6-cis-methyl-HPI and 6 ml. triethylamine in 100 ml. chloroform,whereby the temperature increases to 50° C. After an hour, the reactionmixture is washed with water and then worked up as usual to give2-(4-nitrobenzoyl)-4-oxo-6-cis-methyl-HPI which, after recrystallizationfrom ethanol, melts at 225° - 226° C.

The following compounds are obtained analogously by acylating theappropriate compounds which are unsubstituted in the 2-posiion:

1-methyl-2-(3-nitrobenzoyl)-4-oxo-HPI

2-(3-nitrobenzoyl)-3-methyl-4-oxo-HPI

2-(3-nitrobenzoyl)-4-oxo-6-cis-methyl-HPI; m.p. 184°- 185° C.

2-(3-nitrobenzoyl)-4-oxo-6-trans-methyl-HPI; m.p. 90° - 92° C.

2-(3-nitrobenzoyl)-4-oxo-7-methyl-HPI

2-(3-nitrobenzoyl)-4-oxo-8-methyl-HPI

2-(3-nitrobenzoyl)-4-oxo-8-nitro-HPI

2-(3-nitrobenzoyl)-4-oxo-8-fluoro-HPI

2-(3-nitrobenzoyl)-4)-oxo-8-chloro-HPI

2-(3-nitrobenzoyl)-4-oxo-9-methyl-HPI

2-(3-nitrobenzoyl)-4-oxo-9-nitro-HPI

2-(3-nitrobenzoyl)-4-oxo-9-fluoro-HPI

2-(3-nitrobenzoyl)-4-oxo-9-chloro-HPI

2-(3-nitrobenzoyl)-4-oxo-10-methyl-HPI

2-(3-nitrobenzoyl)-4-oxo-10-nitro-HPI

2-(3-nitrobenzoyl)-4-oxo-10-fluoro-HPI

2-(3-nitrobenzoyl)-4-oxo-10-chloro-HPI

2-(3-nitrobenzoyl)-4-oxo-11-methyl-HPI

2-(3-nitrobenzoyl)-4-oxo-11-nitro-HPI

2-(3-nitrobenzoyl)-4-oxo-11-fluoro-HPI

2-(3-nitrobenzoyl)-4-oxo-11-chloro-HPI

2-(3-nitrobenzoyl)-4-oxo-11b-methyl-HPI

1-methyl-2-(4-nitrobenzoyl)-4-oxo-HPI

2-(4-nitrobenzoyl)-3-methyl-4-oxo-HPI

2-(4-nitrbenzoyl)-4-oxo-6-trans-methyl-HPI

2-(4-nitrobenzoyl)-4-oxo-7-methyl-HPI

2-(4-nitrobenzoyl)-4-oxo-8-methyl-HPI

2-(4-nitrobenzoyl)-4-oxo-8-nitro-HPI

2-(4-nitrobenzoyl)-4-oxo-8-fluoro-HPI

2-(4-nitrobenzoyl)-4-oxo-8-chloro-HPI

2-(4-nitrobenzoyl)-4-oxo-9-methyl-HPI

2-(4-nitrobenzoyl)-4-oxo-9-nitro-HPI

2-(4-nitrobenzoyl)-4-oxo-9-fluoro-HPI

2-(4-nitrobenzoyl)-4-oxo-9-chloro-HPI

2-(4-nitrobenzoyl)-4-oxo-10-methyl-HPI

2-(4-nitrobenzoyl)-4-oxo-10-nitro-HPI

2-(4-nitrobenzoyl)-4-oxo-10-fluoro-HPI

2-(4-nitrobenzoyl)-4-oxo-10-chloro-HPI

2-(4-nitrobenzoyl)-4-oxo-11-methyl-HPI

2-(4-nitrobenzoyl)-4-oxo-11-nitro-HPI

2-(4-nitrobenzoyl)-4-oxo-11-fluoro-HPI

2-(4-nitrobenzoyl)-4-oxo-11-chloro-HPI

2-(4-nitrobenzoyl)-4-oxo-11b-methyl-HPI

1-methyl-2-(2-fluorobenzoyl)-4-oxo-HPI

2-(2-fluorobenzoyl)-3-methyl-4-oxo-HPI

2-(2-fluorobenzoyl)-4-oxo-6-cis-methyl-HPI

2-(2-fluorobenzoyl)-4-oxo-6-trans-methyl-HPI

2-(2-fluorobenzoyl)-4-oxo-7-methyl-HPI

2-(2-fluorobenzoyl)-4-oxo-8-methyl-HPI

2-(2-fluorobenzoyl)-4-oxo-8-nitro-HPI

2-(2-fluorobenzoyl)-4-oxo-8-fluoro-HPI

2-(2-fluorobenzoyl)-4-oxo-8-chloro-HPI

2-(2-fluorobenzoyl)-4-oxo-9-methyl-HPI

2-(2-fluorobenzoyl)-4-oxo-9-nitro-HPI

2-(2-fluorobenzoyl)-4-oxo-9-fluoro-HPI

2-(2-fluorobenzoyl)-4-oxo-9-chloro-HPI

2-(2-fluorobenzoyl)-4-oxo-10-methyl-HPI

2-(2-fluorobenzoyl)-4-oxo-10-nitro-HPI2-(2-fluorobenzoyl)-4-oxo-10-fluoro-HPU

2-(2-fluorobenzoyl)-4-oxo-10-chloro-HPI

2-(2-fluorobenzoyl)-4-oxo-11-methyl-HPI

2-(2-fluorobenzoyl)-4-oxo-11-nitro-HPI

2-(2-fluorobenzoyl)-4-oxo-fluoro-HPI

2-(2-fluorobenzoyl)-4-oxo-11-chloro-HPI

2-(2-fluorobenzoyl)-4-oxo-11b-methyl-HPI

1-methyl-2-(3-fluorobenzoyl)-4-oxo-HPI

2-(3-fluorobenzoyl)-3-methyl-4-oxo-HPI

2-(3-fluorobenzoyl)-4-oxo-6-cis-methyl-HPI

2-(3-fluorobenzoyl)-4-oxo-6-trans-methyl-HPI

2-(3-fluorobenzoyl)-4-oxo-7-methyl-HPI

2-(3-fluorobenzoyl)-4-oxo-7-methyl-HPI

2-(3-fluorobenzoyl)-4-oxo-8-methyl-HPI

2-(3-fluorobenzoyl)-4-oxo-8-nitro-HPI

2-(3-fluorobenzoyl)-4-oxo-8-fluoro-HPI

2-(3-fluorobenzoyl)-4-oxo-8-chloro-HPI

2-(3-fluorobenzoyl)-4-oxo-9-nitro-HPI

2-(3-fluorobenzoyl)-4-oxo-9-fluoro-HPI

2-(3-fluorobenzoyl)-4-oxo--chloro-HPI

2-(3-fluorobenzoyl)-4-oxo-10-nitro-HPI

2-(3-fluorobenzoyl)-4-oxo-10-fluoro-HPI

2-(3-fluorobenzoyl)-4-oxo-10-chloro-HPI

2-(3-fluorobenzoyl)-4-oxo-11-nitro-HPI

2-(3-fluorobenzoyl)-4-oxo-11-fluoro-HPI

2-(3-fluorobenzoyl)-4-oxo-11-chloro-HPI

2-(4-fluorobenzoyl)-4-oxo-8-nitro-HPI

2-(4-fluorobenzoyl)-4-oxo-8-fluoro-HPI

2-(4-fluorobenzoyl)-4-oxo-8-chloro-HPI

2-(4-fluorobenzoyl)-4-oxo-9-nitro-HPI

2-(4-fluorobenzoyl-4-oxo-9-fluoro-HPI

2-(4-fluorobenzoyl)-4-oxo-9-chloro-HPI

2-(4-fluorobenzoyl)-4-oxo-10-nitro-HPI

2-(4-fluorobenzoyl)-4-oxo-10-fluoro-HPI

2 -(4-fluorobenzoyl)-4-oxo-10-chloro-HPI

2-(4-fluorobenzoyl)-4-oxo-11-nitro-HPI

2-(4-fluorobenzoyl)-4-oxo-11-fluoro-HPI

2-(4-fluorobenzoyl)-4-oxo-11-chloro-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-8-nitro-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-8-fluoro-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-8-chloro-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-9-nitro-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-9-fluoro-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-9-chloro-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-10-nitro-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-10-fluoro-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-10-chloro-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-11-nitro-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-11-fluoro-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-11-chloro-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-8-nitro-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-8-fluoro-HPI

2-(thiacyclohexyl-4-carbonyl)-4-8-chloro-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-9-nitro-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-9-fluoro-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-9-chloro-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-10-nitro-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-10-fluoro-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-10-chloro-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-11-nitro-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-11-fluoro-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-11-chloro-HPI

c. 2.4 g. thionyl chloride are added dropwise at -40° C. to a solutin of2.9 g. cyclohexanone-4-carboxylic acid in 20 ml. dimethylformamide and50 ml. dichloromethane, whereafter the reaction mixture is stirred for30 minutes and then 4.3 g 4-oxo-6-trans-methyl-HPI and 4.1 g.triethylamine in 50 ml. dichloromethane are added thereto, followed bystirring for one hour and thereafter working up as usual. There isobtained 2-(4-oxo-cyclohexylcarbonyl)-4-oxo-6-trans-methyl-HPI which,after recrystallization from diethyl ether, melts at 118° - 120° C.

The following compounds are obtained in an analogous manner byacrylation of the appropriate compounds:

1-methyl-2-(cyclohexene-4-carbonyl)-4-oxo-HPI

2-(cyclohexene-4-carbonyl)-3-methyl-4-oxo-HPI

2-(cyclohexene-4-carbonyl)-4-oxo-6-cis-methyl-HPI

2-(cyclohexene-4-carbonyl)-4-oxo-6-trans-methyl-HPI

2-(cyclohexene-4-carbonyl)-4-oxo-7-methyl-HPI

2(cyclohexene-4-carbonyl)-4-oxo-8-methyl-HPI

2-(cyclohexene-4-carbonyl)-4-oxo-8-methyl-HPI

2-(cyclohexene-4-carbonyl)-4-oxo-9-methyl-HPI

2-(cyclohexene-4-carbonyl)-4-oxo-10-methyl-HPI

2-(cyclohexene-4-carbonyl)-4-oxo-11methyl-HPI

2-(cyclohexene-4-carbonyl)-4-oxo-11b-methyl-HPI

d. 1 ml. phosphorus trichloride is added dropwise at 140° C. to asolution of 6.5 g. 4-oxo-6-trans-methyl-HPI and 5 g. 3-nitrobenzoic acidin 50 ml. chlorobenzene. The reaction mixture is boiled for an hour,then evaporated and the residue chromatographed over silica gel withchloroform as elution agent to give2-(3-nitrobenzoyl)-4-oxo-6-trans-methyl-HPI, which melts at 90° - 92° C.

The following compounds are obtained analogously by acylation of theappropriate compounds:

1-methyl-2nicotinoyl-4-oxo-HPI

2-nicotinoyl-3-methyl-4-oxo-HPI

2-nicotinoyl-4-oxo-6-cis-methyl-HPI

2-nicotinoyl-4-oxo-6-trans-methyl-HPI

2-nicotinoyl-4-oxo-7-methyl-HPI

2-nicotinoyl-4-oxo-8-methyl-HPI

2-nicotinoyl-4-oxo-9-methyl-HPI

2-nicotinoyl-4-oxo-10-methyl-HPI

2-nicotinoyl-4-oxo-11-methyl-HPI

2-nicotinoyl-4-oxo-11b-methyl-HPI

1-methyl-2-(2-thienylcarbonyl)-4-oxo-HPI

2-(2-thienylcarbonyl)-3-methyl-4-oxo-HPI

2-(2-thienylcarbonyl)-4-oxo-6-cis-methyl-HPI

2-(2-thienylcarbonyl)-4-oxo-6-trans-methyl-HPI

2-(2-thienylcarbonyl)-4-oxo-7-methyl-HPI

2-(2-thienylcarbonyl)-4-oxo-8-methyl-HPI

2-(2-thienylcarbonyl)-4-oxo-9-methyl-HPI

2-(2-thienylcarbonyl)-4-oxo-10-methyl-HPI

2-(2-thienylcarbonyl)-4-oxo-11-methyl-HPI

2-(2-thienylcarbonyl)-4-oxo-11b-methyl-HPI

1-methyl-2-(3-thienylcarbonyl)-4-oxo-HPI

2-(3-thienylcarbonyl)-3-methyl-4-oxo-HPI

2-(3-thienylcarbonyl)-4-oxo-6-cis-methyl-HPI

2-(3-thienylcarbonyl)-4-oxo-6-trans-methyl-HPI

2-(3-thienylcarbonyl)-4-oxo-7-methyl-HPI

2-(3-thienylcarbonyl)-4-oxo-8-methyl-HPI

2-(3-thienylcarbonyl)-4-oxo-9-methyl-HPI

2-(3-thienylcarbonyl)-4-oxo-10-methyl-HPI

2-(3-thienylcarbonyl)-4-oxo-11-methyl-HPI

2-(3-thienylcarbonyl)-4-oxo-11b-methyl-HPI

e. A solution of 6.5 g. 4-oxo-6-cis-methyl-HPI, 4.8 g. isobutyric acidanhydride and 2.2 g. triethylamine in 100 ml. dichloromethane is left tostand overnight at 20° C., whereafter the reaction mixture is worked upas usual to give 2-isobutyryl-4-oxo-6-cis-methyl-HPI, which melts at136° C.

f. 5 g. 4-oxo-6-cis-methyl-HPI, 4 g. 3-nitrobenzoic acid and 3 g.silicon tetrachloride in 100 m. pyridine are boiled for an hour, thenpoured on to ice and worked up as usual to give2-(3-nitrobenzyl)-4-oxo-6-cis-methyl-HPI, which melts at 184°-185° C.

g. 3.3 g. (2-cyclohexane-4-carbonyl)-4-oxo-6-trans-methyl-HPI in 100 ml.tetrahydrofuran are hydrogenated on 0.3 g. platinum oxide at 20° C. andat atmospheric pressure, whereafter the solvent is distilled off to give2-cyclohexylcarbonyl-4-oxo-6-trans-methyl-HPI, which melts at 134° C.

EXAMPLE 3

Crude1-(N-benzoyl-N-carboxymethylaminomethyl)-4-methyl-1,2,3,4-tetrahydroisoquinoline,obtained by the reaction of 1.4 g. 2-phenylpropylamine with 2.7 g.N-(2,2-dimethoxyethyl)-N-carboxymethylbenzamide (obtainable by thereaction of trimethylsilyl hippurate with trimethylsilylchloride/triethylamine and chloroacetaldehyde dimethyl acetal) in 20 ml.concentrated hydrochloride at 70° C., is boiled overnight with toluenefor the removal of water. Upon cooling, 2-benzoyl-4-oxo-7-methyl-HPIcrystallizes out. It melts at 157° C.

In an analogous manner, from1-(N-benzoyl-N-carboxymethylaminoethyl)-4-phenyl-1,2,3,4-tetrahydroisoquinoline(obtainable from 2,2-diphenylethylamine), there is obtained2-benzoyl-4-oxo-7-phenyl-HPI.

EXAMPLE 4

3.4 g. 1-benzoyl-3-oxo-4-(2-hydroxyethyl)-5-p-tolylpiperazine(obtainable by the reaction of p-tolylglyoxal bisulfite adduct withaminomalondiamide to give 2-aminocarbonyl-3-hydroxy-5-p-tolylpyrazine,saponification and decarboxylation to 3-hydroxy-5-p-tolylpyrazine,hydrogenation to 3-oxo-5-p-tolylpiperazine, reaction with benzoylchloride to give 1-benzoyl-3-oxo-5-p-tolylpiperazine and reaction withethylene oxide in the presence of sodium hydroxide) in about 50 ml.liquid hydrogen fluoride is left to stand for 3 days at 20° C.,whereafter the reaction mixture is poured into ice water and then workedup as usual to give 2-benzoyl-4-oxo-9-methyl-HPI, which has a meltingpoint of 162°-163° C.

EXAMPLE 5

3.6 g. 1-benzoyl-3-oxo-4-(2-chloroethyl)-5-p-tolylpiperazine (obtainablefrom 1-benzoyl-3-oxo-4-(2-hydroxyethyl)-5-p-tolylpiperazine by reactionwith thionyl chloride) in 50 ml. carbon disulfide are added, with icecooling, to 0.5 g. aluminum trichloride in 50 ml. carbon disulfide. Thereaction mixture is stirred for 12 hours, then poured on to ice andworked up as usual to give 2-benzoyl-4-oxo-9-methyl-HPI, which melts at162°-163° C.

EXAMPLE 6

a. 3.37 g. 1-benzoyl-3-oxo-5-phenyl-piperazinyl-4-acetic acid aredissolved in 15 ml. liquid hydrogen fluoride, wherafter the solution isleft to stand for 2 days, then poured on to ice. After the usual workingup, there is obtained 2-benzoyl-4,7-dioxo-HPI.

b. 3.2 g. 2-benzoyl-4,7-dioxo-HPI are dissolved in 60 ml. methanol, 0.5g. sodium borohydride is added thereto portionwise at 0° C. and thereaction mixture is stirred for 12 hours at 20° C. and poured on to ice.There is thus obtained 2-benzoyl-4-oxo-7-hydroxy-HPI.

c. 3.22 g. 2-benzoyl-4-oxo-7-hydroxy-HPI are dissolved in 20 ml.chloroform and subsequently 1.3 g. thionyl chloride in 5 ml. chloroformadded thereto dropwise, while stirring. The reaction mixture is boiledfor an hour, then evaporated and, after the usual working up, there isobtained 2-benzoyl-4-oxo-7-chloro-HPI.

EXAMPLE 7

a. 3.70 g. 1-benzoyl-3-oxo-4-chlorocarbonylmethyl-5-p-tolyl-piperazineare dissolved in 50 ml. nitrobenzene, 1.4 g. aluminium trichloride areadded thereto and the reaction mixture is stirred overnight at 20° C.,whereafter, after the usual working up, there is obtained2-benzoyl-4,7-dioxo-9-methyl-HPI.

b. 3.34 g. 2-benzoyl-4,7-dioxo-9-methyl-HPI, 1.5 g. potassium hydroxide,3 ml. 35% hydrazine and 25 ml. diethylene glycol are heated to 100° C.for an hour and the temperature is then slowly increased until thehydrazone formed is destroyed, whereby excess hydrazine and waterevaporate off, whereafter the reaction mixture is boiled for 4 hours.The reaction mixture is then cooled and, after the usual working up,there is obtained 2-benzoyl-4-oxo-9-methyl-HPI, which melts at 162°-163°C.

c. 3.6 g. 2-benzoyl-4-oxo-7-chloro-9-methyl-HPI (obtainable by thehydrogenation of 2-benzoyl-4,7-dioxo-9-methyl-HPI in the presence ofRaney nickel to give 2-benzoyl-4-oxo-7-hydroxy-9-methyl-HPI andsubsequent reaction with thionyl chloride) are hydrogenated in 100 ml.methanol and in the presence of 0.3 g. palladium charcoal at 20° C. andat atmospheric pressure, whereafter the solution is concentrated. Afterthe solution of diethyl ether, there is obtained2-benzoyl-4-oxo-9-methyl-HPI, which melts at 162°-163° C.

EXAMPLE 8

3.2 g.2-benzoyl-4-oxo-9-methyl-2,3,6,7-tetrahydro-4H-pyrazino[2,1-a]isoquinoline(obtainable by the cyclization of1-(2-m-tolylethyl)-4-benzoyl-piperazine-2,6-dione with polyphosphoricacid) are hydrogenated in 200 ml. methanol in the presence of 1.5 g.Raney nickel at 20° C. and at atmospheric pressure. After evaporation ofthe solvent, there is obtained 2-benzoyl-4-oxo-9-methyl-HPI, which meltsat 162°-163° C.

EXAMPLE 9

3.2 g. 2-benzoyl-4-oxo-7-methylene-HPI (obtainable from3-hydroxy-5-phenyl-pyrazine by hydrogenation to give3-oxo-5-phenyl-piperazine, reaction with benzoyl chloride to give1-benzoyl-3-oxo-5-phenyl-piperazine, reaction with trimethylsilylchloride/triethylamine and trimethylsilyl chloroacetate to give1-benzoyl-3-oxo-5-phenyl-piperazinyl-4-acetic acid, cyclization withhydrogen fluoride to give 2-benzoyl-4,7-dioxo-HPI and reaction withmethylene triphenyl phosphorane in diethyl ether) are hydrogenated in100 ml. ethanol in the presence of 1 g. 5% palladium charcoal at 40° C.and at atmospheric pressure and then filtered and the filtrateevaporated to give 2-benzoyl-4-oxo-7-methyl-HPI, which melts at 157° C.

EXAMPLE 10

3.2 g.2-benzoyl-4-oxo-9-methyl-1,2,3,11b-tetrahydro-4H-pyrazino[2,1-a]isoquinoline(obtainable from 1-benzoyl-3-oxo-5-p-tolyl-piperazine by reaction withtrimethylsilyl cloride/triethylamine and trimethylsilyl chloroacetate togive 1-benzoyl-3-oxo-4-carboxymethyl-5-p-tolyl-piperazine, reaction withliquid hydrogen fluoride to give 2-benzoyl-4,7-dioxo-9-methyl-HPI andreaction with trimethylsilyl chloride/zinc in diethyl ether) arehydrogenated in 50 ml. tetrahydrofuran in the presence of 200 mg.platinum oxide at 20° C. and at atmospheric pressure, followed byfiltration and evaporation of the filtrate to give2-benzoyl-4-oxo-9-methyl-HPI, which melts at 162°-163° C.

EXAMPLE 11

5.7 g. 3-chloroperbenzoic acid are added portionwise to 4.6 g.2-(pyridyl-2-carbonyl)-4-oxo-HPI in 270 ml. dichloromethane and thereaction mixture then left to stand for 24 hours at 20° C. Ammonia isthen passed in, the reaction mixture is filtered with suction and thesolvent is evaporated off from the filtrate to give1-hydroxy-2-(pyridyl-2-carbonyl)-4-oxo-HPI which, afterrecrystallization from acetone, melts at 140° C.

EXAMPLE 12

76.5 g. 2-benzoyl-4-oxo-HPI in 1 liter anhydrous tetrahydrofuran areadded dropwise to a suspension of sodamide, prepared from 5.75 g. sodiumin 1250 ml. liquid ammonia, whereafter the reaction mixture is stirredfor an hour, 32 ml. ethylene oxide are added thereto and the reactionmixture is stirred overnight. It is then allowed to come to ambienttemperature and the solvent is distilled off. After the usual workingup, there is obtained a resin which is chromatographically purified oversilica gel, using chloroform as elution agent. There is obtained2-benzoyl-3-(2-hydroxyethyl)-4-oxo-HPI which, after recrystallizationfrom ethyl acetate/diethyl ether, melts at 194° C.

EXAMPLE 13

3.12 g. 2-cyclohexylcarbonyl-4-oxo-HPI are dissolved in 50 ml.chloroform, a solution of 1.6 g. bromine in 20 ml. chloroform is addeddropwise thereto, while stirring, at 20° C. and the reaction mixture isstirred overnight. After the usual working up, there is obtained2-cyclohexylcarbonyl-4-oxo-8(?)-bromo-HPI (the position of the bromineatom is not definite). Other bromination products are thereby alsoformed.

EXAMPLE 14

a. A solution of 31.2 g. 2-cyclohexylcarbonyl-4-oxo-HPI in 50 ml. aceticacid is added to 10° C. to 100 g. of fuming sulfuric acid (30% by weightof sulfur trioxide), cooled to 0° C. and 5 ml. nitric acid (D = 1.52) in10 ml. acetic acid added dropwise thereto at a temperature below 20° C.The reaction mixture is stirred for an hour at 10°-20° C., hydrolyzedwith ice water and extracted with chloroform. The chloroform extract ispurified chromatographically on silica gel, using ethyl acetate aselution agent. There is obtained 2-cyclohexylcarbonyl-4-oxo-11(or8)-nitro-HPI (R_(f) value about 0.4) and 2-cyclohexylcarbonyl-4-oxo-8(or11)-nitro-HPI (R_(f) value 0.25). Both compounds exhibit infra-red bandsat 1660, 1530, 1350 and 750 cm⁻¹ and mass peaks at m/e = 246; 357.

The following compounds are obtained analogously by the nitration of thecorresponding compounds which are unsubstituted in the 8- and11-positions:

1-methyl-2-cyclohexylcarbonyl-4-oxo-8(or 11)-nitro-HPI

1-methyl-2-cyclohexylcarbonyl-4-oxo-11(or 8)-nitro-HPI

2-cyclohexylcarbonyl-3-methyl-4-oxo-8(or 11)-nitro-HPI

2-cyclohexylcarbonyl-3-methyl-4-oxo-11(or 8)-nitro-HPI

2-cyclohexylcarbonyl-4-oxo-6-cis-methyl-8(or 11)-nitro-HPI

2-cyclohexylcarbonyl-4-oxo-6-cis-methyl 11(or 8) nitro-HPI

2-cyclohexylcarbonyl-4-oxo-6-trans-methyl-8(or 11)-nitro-HPI

2-cyclohexylcarbonyl-4-oxo-6-trans-methyl-11(or 8)-nitro-HPI

2-cyclohexylcarbonyl-4-oxo-7-methyl-8(or 11)-nitro-HPI

2-cyclohexylcarbonyl-4-oxo-7-methyl-11(or 8)-nitro-HPI

2-cyclohexylcarbonyl-4-oxo-8(or 11)-nitro-9-methyl-HPI

2-cyclohexylcarbonyl-4-oxo-9-methyl-11(or 8)-nitro-HPI

2-cyclohexylcarbonyl-4-oxo-8(or 11)-nitro-10-methyl-HPI

2-cyclohexylcarbonyl-4-oxo-10-methyl-11(or 8)-nitro-HPI

2-cyclohexylcarbonyl-4-oxo-8(or 11)-nitro-11b-methyl-HPI

2-cyclohexylcarbonyl-4-oxo-11(or 8)-nitro-11b-methyl-HPI

1-methyl-2-(tetrahydropyranyl-4-carbonyl)-4-oxo-8(or 11)-nitro-HPI

1-methyl-2-(tetrahydropyranyl-4-carbonyl)-4-oxo-11(or 8)-nitro-HPI

2-(tetrahydropyranyl-4-carbonyl)-3-methyl-4-oxo-8(or 11)-nitro-HPI

2-(tetrahydropyranyl-4-carbonyl)-3-methyl-4-oxo-11(or 8)-nitro-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-6-cis-methyl-8(or 11)-nitro-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-6-cis-methyl-11(or 8)-nitro-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-6-trans-methyl-8(or 11)-nitro-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-6-trans-methyl-11(or 8)-nitro-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-7-methyl-8(or 11)-nitro-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-7-methyl-11(or 8)-nitro-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-8(or 11)-nitro-9-methyl-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-9-methyl-11(or 8)-nitro-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-8(or 11)-nitro-10-methyl-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-10-methyl-11(or 8)-nitro-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-8(or 11)-nitro-11b-methyl-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-oxo-11(or 8)-nitro-11b-methyl-HPI

1-methyl-2-(thiacyclohexyl-4-carbonyl)-4-oxo-8(or 11)-nitro-HPI

1-methyl-2-(thiacyclohexyl-4-carbonyl)-4-oxo-11(or 8)-nitro-HPI

2-(thiocyclohexyl-4-carbonyl)-3-methyl-4-oxo-8(or 11)-nitro-HPI

2-(thiacyclohexyl-4-carbonyl)-3-methyl-4-oxo-11(or 8)-nitro-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-6-cis-methyl-8(or 11)-nitro-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-6-cis-methyl-11(or 8)-nitro-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-6-trans-methyl-8(or 11)-nitro-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-6-trans-methyl-11(or 8)-nitro-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-7-methyl-8(or 11)-nitro-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-7-methyl-11(or 8)-nitro-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-8(or 11)-nitro-9-methyl-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-9-methyl-11(or 8)-nitro-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-8(or 11)-nitro-10-methyl-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-10-methyl-11(or 8)-nitro-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-8(or 11)-nitro-11b-methyl-HPI

2-(thiacyclohexyl-4-carbonyl)-4-oxo-11(or 8)-nitro-11b-methyl-HPI

2-benzoyl-4-oxo-8(or 11)-nitro-HPI

2-benzoyl-4-oxo-11(or 8)-nitro-HPI

2-(3-fluorobenzoyl)-4-oxo-8(or 11)-nitro-HPI

2-(3-fluorobenzoyl)-4-oxo-11(or 8)-nitro-HPI

2-(4-fluorobenzoyl)-4-oxo-8(or 11)-nitro-HPI

2-(4-fluorobenzoyl)-4-oxo-11(or 8)-nitro-HPI

2-(3-nitrobenzoyl)-4-oxo-8(or 11)-nitro-HPI

2-(3-nitrobenzoyl)-4-oxo-11(or 8)-nitro-HPI

2-(4-nitrobenzoyl)-4-oxo-8(or 11)-nitro-HPI

2-(4-nitrobenzoyl)-4-oxo-11(or 8)-nitro-HPI

b. 4.1 g. 2-cyclohexylcarbonyl-4-oxo-11(or 8)-nitro-HPI are hydrogenatedin 100 ml. methanol in the presence of 2 g. 5% palladium charcoal at 20°C. and at atmospheric pressure. After filtration and evaporation of thesolvent, the residue is chromatographed on silica gel, usingchloroform/methanol (98:2) as elution agent. There is obtained2-cyclohexylcarbonyl-4-oxo-11(or 8)-amino-HPI which, afterrecrystallization from benzene/petroleum ether, melts at 160°-162° C.

The following compounds are obtained analogously by hydrogenation of theappropriate nitro compounds:

2-cyclohexylcarbonyl-4-oxo-8(or 11)-amino-HPI

1-methyl-2-(3-aminobenzoyl)-4-oxo-HPI

2-(3-aminobenzoyl)-3-methyl-4-oxo-HPI

2-(3-aminobenzoyl)-4-oxo-6-cis-methyl-HPI hydrochloride; m.p. 195° C.

2-(3-aminobenzoyl)-4-oxo-6-trans-methyl-HPI hydrochloride; m.p. 205° C.

2-(3-aminobenzoyl)-4-oxo-7-methyl-HPI

2-(3-aminobenzoyl)-4-oxo-8-methyl-HPI

2-(3-aminobenzoyl)-4-oxo-8-amino-HPI

2-(3-aminobenzoyl)-4-oxo-8-fluoro-HPI

2-(3-aminobenzoyl)-4-oxo-8-chloro-HPI

2-(3-aminobenzoyl)-4-oxo-9-methyl-HPI

2-(3-aminobenzoyl)-4-oxo-9-amino-HPI

2-(3-aminobenzoyl)-4-oxo-9-fluoro-HPI

2-(3-aminobenzoyl)-4-oxo-9-chloro-HPI

2-(3-aminobenzoyl)-4-oxo-10-methyl-HPI

2-(3-aminobenzoyl)-4-oxo-10-amino-HPI

2-(3aminobenzoyl)-4-oxo-10-fluoro-HPI

2-(3-aminobenzoyl)-4-oxo-10-chloro-HPI

2-(3-aminobenzoyl)-4-oxo-11-methyl-HPI

2-(3-aminobenzoyl)-4-oxo-11-amino-HPI

2-(3-aminobenzoyl)-4-oxo-11-fluoro-HPI

2-(3-aminobenzoyl)-4-oxo-11-chloro-HPI

2-(3-aminobenzoyl)-4-oxo-11b-methyl-HPI

1-methyl-2-(4-aminobenzoyl)-4-oxo-HPI

2-(4-aminobenzoyl)-3-methyl-4-oxo-HPI

2-(4-aminobenzoyl)-4-oxo-6-cis-methyl-HPI, ethanol solvate, m.p. 226° C.

2-(4-aminobenzoyl)-4-oxo-6-trans-methyl HPI

2-(4-aminobenzoyl)-4-oxo-7-methyl-HPI

2-(4-aminobenzoyl)-4-oxo-8-methyl-HPI

2-(4-aminobenzoyl)-4-oxo-8-amino-HPI

2-(4-aminobenzoyl)-4-oxo-8-fluoro-HPI

2-(4-aminobenzoyl)-4-oxo-8-chloro-HPI

2-(4-aminobenzoyl)-4-oxo-9-methyl-HPI

2-(4-aminobenzoyl)-4-oxo-9-amino-HPI

2-(4-aminobenzoyl)-4-oxo-9-fluoro-HPI

2-(4-aminobenzoyl)-4-oxo-9-chloro-HPI

2-(4-aminobenzoyl)-4-oxo-10-methyl-HPI

2-(4-aminobenzoyl)-4-oxo-10-amino-HPI

2-(4-aminobenzoyl)-4-oxo-10-fluoro-HPI

2-(4-aminobenzoyl)-4-oxo-10-chloro-HPI

2-(4-aminobenzoyl)-4-oxo-11-methyl-HPI

2-(4-aminobenzoyl)-4-oxo-11-amino-HPI

2-(4-aminobenzoyl)-4-oxo-11-fluoro-HPI

2-(4-aminobenzoyl)-4-oxo-11-chloro-HPI

2-(4-aminobenzoyl)-4-oxo-11b-methyl-HPI

2-(3-aminobenzoyl)-4-thioxo-HPI

2-(4-aminobenzoyl)-4-thioxo-HPI

2-(4-methylaminobenzoyl)-4-thioxo-HPI

2-(4-n-butylaminobenzoyl)-4-thioxo-HPI

c. A solution of 4.9 g. 2-cyclohexylcarbonyl-4-oxo-8(or 11)-amino-HPIand 1.5 g. 35% formaldehyde solution in 200 ml. methanol is hydrogenatedin the presence of 1 g. 5% palladium charcoal at 20° C. and atatospheric pressure. Subsequently, the reaction mixture is filtered andevaporated and the residue is purified by chromatographing over silicagel, using chloroform as elution agent. There is obtained2-cyclohexylcarbonyl-4-oxo-8(or 11)-methyl-amino-HPI.

The following compounds are obtained analogously from the appropriateprimary amines:

2-cyclohexylcarbonyl-4-oxo-11(or 8)-methylamino-HPI

2-(3-methylaminobenzoyl)-4-oxo-6-cis-methyl-HPI

2-(3-methylaminobenzoyl)-4-oxo-6-trans-methyl-HPI

2-(4-methylaminobenzoyl)-4-oxo-6-cis-methyl-HPI

d. In a manner analogous to that described in c) above, from 4.9 g.2-cyclohexylcarbonyl-4-oxo-8(or 11)-amino-HPI and 4 g. 33% formaldehydesolution, there is obtained 2-cyclohexylcarbonyl-4-oxo-8(or11)-dimethylamino-HPI.

The following compounds are obtained analogously from the correspondingprimary or secondary amines:

2-cyclohexylcarbonyl-4-oxo-11(or 8)-dimethylamino-HPI

2-(3-dimethylaminobenzoyl)-4-oxo-6-cis-methyl-HPI

2-(3-dimethylaminobenzoyl)-4-oxo-6-trans-methyl-HPI

2-(4-dimethylaminobenzoyl)-4-oxo-6-cis-methyl-HPI

e. Over a period of 2 hours, 3.3 g. 2-cyclohexylcarbonyl-4-oxo-8(or11)-amino-HPI in 100 ml. dioxane are mixed with 2.5 g. dimethyl sulfateand the reaction mixture substantially stirred at 100° C. for 15 hours.1.4 g. potassium hydroxide in 5 ml. water are then stirred into thecooled solution. After the usual working up, there is obtained2-cyclohexylcarbonyl-4-oxo-8(or 11)-dimethylamino-HPI.

In an analogous manner, with the use of diethyl sulfate and n-butylbromide, there are obtained the following compounds:

2-cyclohexylcarbonyl-4-oxo-8(or 11)-dimethylamino-HPI

2-cyclohexylcarbonyl-4-oxo-8(or 11)-di-n-butylamino-HPI.

f. 4.2 g. 2-cyclohexylcarbonyl-4-oxo-8(or 11)-trifluoroacetamido-HPI(preferable by the reaction of 2-cyclohexylcarbonyl-4-oxo-8(or11)-amino-HPI with trifluoroacetic anhydride/triethylamine indichloromethane) are heated with 11.4 g. methyl iodide in 100 ml. dryacetone almost to boiling. 4.5 g. pulverized potassium hydroxide arethen added thereto, followed by heating to the boil for 5 minutes,whereafter the reaction mixture is evaporated, the residue is mixed withwater, stirred for 2 hours at 20° C. and then worked up as usual to give2-cyclohexylcarbonyl-4-oxo-8(or 11)-methylamino-HPI.

If the methyl iodide is not removed before the hydrolysis, then there isobtained 2-cyclohexylcarbonyl-4-oxo-8(or 11)-dimethylamino-HPI.

g. 9.8 g. 2-cyclohexylcarbonyl-4-oxo-8(or 11)-amino-HPI and 1.5 g.formic acid in 100 ml. toluene are heated for 5 hours, with a waterseparator, then evaporated to dryness and, after trituration of theresidue with diethyl ether, there is obtained2-cyclohexylcarbonyl-4-oxo-8(or 11)-formamido-HPI.

h. 2.4 g. acetyl chloride in 50 ml. chloroform are added to 9.8 g.2-cyclohexylcarbonyl-4-oxo-8(or 11)-amino-HPI and 3.1 g. triethylaminein 300 ml. chloroform and the reaction mixture is heated for 3 hours andthen worked up as usual to give 2-cyclohexylcarbonyl-4-oxo-8(or11)-acetamido-HPI.

The following compounds are obtained in an analogous manner withpropionyl chloride and butyryl chloride:

2-cyclohexylcarbonyl-4-oxo-8(or 11)-propionamido-HPI

2-cyclohexylcarbonyl-4-oxo-8(or 11)-butyramido-HPI.

i. The diazonium fluoroborate prepared from 3.3 g2-cyclohexylcarbonyl-4-oxo-8(or 11)-amino-HPI, 8 ml. 35%tetrafluoroboric acid, 0.7 g. sodium nitrite and 4 ml. water is filteredoff, washed with 5% tetrafluoroboric acid, with a little ethanol andwith diethyl ether, dried and decomposed at 130°-150° C. There isobtained 2-cyclohexylcarbonyl-4-oxo-8(or 11)-fluoro-HPI. Mass spectrum:m/e = 219; 330.

j. The aqueous suspension of the diazonium fluoroborate obtainedaccording to (i) above is irradiated with a high pressure mecury lampuntil the evolution of gas is finished. The reaction mixture is thenextracted with chloroform and again there is obtained2-cyclohexylcarbonyl-4-oxo-8(or 11)-fluoro-HPI.

k. 2.5 g. 2-cyclohexylcarbonyl-4-oxo-8(or 11)-amino-HPI are diazotisedin 3 ml. 25% hydrochloric acid at about 0°-5° C. with a solution of 0.52g. sodium nitrite in 3 ml. water. The diazonium solution is addeddropwise,, with stirring, to a mixture of 1 g. cuprous chloride in 4 ml.concentrated hydrochloric acid. The reaction mixture is slowly heated toabout 90° C. until the evolution of gas has finished, followed bycooling, extraction with chloroform and purification of the organicphase chromatographically on silica gel to give2-cyclohexylcarbonyl-4-oxo-8(or 11)-chloro-HPI; mass spectrum: m/e =235; 346.

1. A diaxonium solution prepared from 3.3 g.2-cyclohexylcarbonyl-4-oxo-8(or 11)-amino-HPI, 1.4 ml. concentratedsulfuric acid, 5 ml. water and 0.87 g. sodium nitrite is added, withstirring, to a solution of 4 g. potassium cyanide and 3.4 g. coppersulfate in 40 ml. water, buffered with 3.5 g. sodium bicarbonate. Thereaction mixture is left to stand for half an hour and then worked up asusual to give 2-cyclohexylcarbonyl-4-oxo-8(or 11)-cyano-HPI; massspectrum: m/e = 226; 337.

m. 2.5 g. 2-cyclohexylcarbonyl-4-oxo-8(or 11)-amino-HPI are dissolved in3 ml. 25% hydrochloric acid and a solution of 0.52 g. sodium nitrite in3 ml. water added thereto. The diazonium salt solution is introducedwith stirring, into 50 ml. boiling water. Subsequently, it it boiled for30 minutes and then worked up as usual to give2-cyclohexylcarbonyl-4-oxo-8(or 11)-hydroxy-HPI.

The following compounds are obtained in an analogous manner:

2-cyclohexylcarbonyl-4-oxo-11(or 8)-hydroxy-HPI

2-(3-hydroxybenzoyl)-4-oxo-6-cis-methyl-HPI

2-(3-hydroxybenzoyl)-4-oxo-6-trans-methyl-HPI

2-(4-hydroxybenzoyl)-4-oxo-6-cis-methyl-HPI

n. A diazonium salt solution prepared from 3.3 g.2-cyclohexylcarbonyl-4-oxo-8(or 11)-amino-HPI, 5 ml. 6N hydrochloricacid, 0.7 g. sodium nitrite and 4 ml. water is allowed to run into asolution of 1.4 g. salicyclic acid in 15 ml. 2N aqueous hydroxidesolution at 5°-10° C. After 30 minutes, the product obtained isprecipitated out with hydrochloric acid, filtered off, washed with waterand a little ethanol and dried. There is obtained orange-red2-cyclohexylcarbonyl-4-oxo-8(or 11)-(3-carboxy-4-hydroxyphenylazo)-HPI.

The following compounds are obtained in an analogous manner withdimethylaniline, 2-naphthol-6-sulfonic acid and 2-methylanisole:

2-cyclohexylcarbonyl-4-oxo-8(or 11)-(4-dimethylaminophenylazo)-HPI

2-cyclohexylcarbonyl-4-oxo-8(or11)-(2-hydroxy-6-sulpho-1-naphthylazo)-HPI

2-cyclohexylcarbonyl-4-oxo-8(or 11)-3-methyl-4-methoxyphenylazo-HPI.

the following compounds are also obtained in an analogous manner fromdiazotised 2-(3-aminobenzoyl)-4-oxo-6-trans-methyl-HPI with phenol ormethylaniline:

2-(3-p-hydroxyphenylazobenzoyl)-4-oxo-6-trans-methyl-HPI

2-(3-p-methylaminophenylazobenzoyl)-4-oxo-6-trans-methyl-HPI

EXAMPLE 15

a. 20.2 g. 4-oxo-HPI in 500 ml. dioxan are heated to the boil and 20 g.phosphorus pentasulfide are added thereto portionwise within the courseof 2 hours. The reaction mixture is heated for a further hour, thesolvent is then removed and the residue is worked up as usual. Theresidue obtained is purified chromatographically over silica gel, usingchloroform/methanol (95:5) as elution agent. There is obtained4-thioxo-HPI which, after recrystallization from benzene, melts at 151°C.

In an analogous manner, with excess phosphorus pentasulfide, there isobtained from 2-cyclohexylcarbonyl-4-oxo-HPI,2-cyclohexylthiocarbonyl-4-thioxo-HPI and from 2-benzoyl-4-oxo-HPI, 2-thiobenzoyl-4-thioxo-HPI.

b. 1.6 g. benzoyl chloride in 50 ml. chloroform are added to a solutionof 2.2 g. 4-thioxo-HPI and 1.1 g. triethylamine in 100 ml. chloroformand the reaction mixture is stirred for an hour at 20° C. After theusual working up, there is obtained 2-benzoyl-4-thioxo-HPI which, afterrecrystallization from ethanol, melts at 184° C.

The following compounds are obtained analogously with the use of theappropriate acid chlorides:

2-acetyl-4-thioxo-HPI

2-cyclopentylcarbonyl-4-thioxo-HPI

2-cyclohexylcarbonyl-4-thioxo-HPI

2-cycloheptylcarbonyl-4-thioxo-HPI

2-(4-oxo-cyclohexyl-carbonyl)-4-thioxo-HPI

2-(tetrahydropyranyl-4-carbonyl)-4-thioxo-HPI

2-(tetrahydrothiopyranyl-4-carbonyl)-4-thioxo-HPI

2-(1-oxo-1-thiacyclohexyl-4-carbonyl)-4-thioxo-HPI

2-(1,1-dioxo-1-thiacyclohexyl-4-carbonyl)-4-thioxo-HPI

2-(3-fluorobenzoyl)-4-thioxo-HPI

2-(4-fluorobenzoyl)-4-thioxo-HPI

2-(3-chlorobenzoyl)-4-thioxo-HPI

2-(4-chlorobenzoyl)-4-thioxo-HPI

2-(3-nitrobenzoyl)-4-thioxo-HPI

2-(4-nitrobenzoyl)-4-thioxo-HPI

2-(4-dimethylaminobenzoyl)-4-thioxo-HPI

12-(4-di-n-butylaminobenzoyl)-4-thioxo-HPI

2-(4-formamidobenzoyl)-4-thioxo-HPI

2-(4-butyramidobenzoyl)-4-thioxo-HPI

2-(2-thienylcarbonyl)-4-thioxo-HPI

2-(3-thionylcarbonyl)-4-thioxo-HPI

2-(2-pyridylcarbonyl)-4-thioxo-HPI

2-nicotinoyl-4-thioxo-HPI

2-isonicotinoyl-4-thioxo-HPI

EXAMPLE 16.

6.4 g. S-thiobenzoyl-mercaptoacetic acid in 15 ml. 2N aqueous sodiumhydroxide solution is added to 6.06 g. 4-oxo-HPI in 150 ml.tetrahydrofuran and the reaction mixture stirred for 12 hours at 20° C.The reaction mixture is worked up as usual to give2-thiobenzoyl-4-oxo-HPI which, after recrystallization fromethanol/petroleum ether, melts at 98°-99° C.

The following compounds are obtained in an analogous manner by thethioacylation of the appropriate compounds which are unsubstituted inthe 2-position:

(+)-2-thiobenzoyl-4-oxo-HPI; m.p. 167°-168° C.; [α]_(D) ²⁰ = + 56.1°

1-methyl-2-thiobenzoyl-4-oxo-HPI

2-thiobenzoyl-3-methyl-4-oxo-HPI

2-thiobenzoyl-4-thioxo-HPI

2-thiobenzoyl-4-oxo-6-cis-methyl-HPI; m.p. 100°-101° C.

2-thiobenzoyl-4-oxo-6-trans-methyl-HPI

2-thiobenzoyl-4-oxo-7-methyl-HPI

2-thiobenzoyl-4-oxo-8-methyl-HPI

2-thiobenzoyl-4-oxo-9-methyl-HPI

2-thiobenzoyl-4-oxo-10-methyl-HPI

2-thiobenzoyl-4-oxo-11-methyl-HPI

2-thiobenzoyl-4-oxo-11b-methyl-HPI

2-(3-fluorothiobenzoyl)-4-oxo-HPI

1-methyl-2-(3-fluorothiobenzoyl)-4-oxo-HPI

2-(3-fluorothiobenzoyl)-3-methyl-4-oxo-HPI

2-(3-fluorothiobenzoyl)-4-thioxo-HPI

2-(3-fluorothiobenzoyl)-4-oxo-6-cis-methyl-HPI

2-(3-fluorothiobenzoyl)-4-oxo-6-trans-methyl-HPI

2-(3-fluorothiobenzoyl)-4-oxo-7-methyl-HPI

2-(3-fluorothiobenzoyl)-4-oxo-8-methyl-HPI

2-(3-fluorothiobenzoyl)-4-oxo-9-methyl-HPI

2-(3-fluorothiobenzoyl)-4-oxo-10-methyl-HPI

2-(34-fluorothiobenzoyl)-4-oxo-11-methyl-HPI

2-(3-fluorothiobenzoyl)-4-oxo-11b-methyl-HPI

2-(4-fluorothiobenzoyl)-4-oxo-HPI

1-methyl-2-(4-fluorothiobenzoyl)-4-oxo-HPI

2-(4-fluorothiobenzoyl)-3-methyl-4-oxo-HPI

2-(4-fluorothiobenzoyl)-4-thioxo-HPI

2-(4-fluorothiobenzoyl)-4-oxo-6-cis-methyl-HPI

2-(4-fluorothiobenzoyl)-4-oxo-6-trans-methyl-HPI

2-(4-fluorothiobenzoyl)-4-oxo-7-methyl-HPI

2-(4-fluorothiobenzoyl)-4-oxo-8-methyl-HPI

2-(4-fluorothiobenzoyl)-4-oxo-9-methyl-HPI

2-(4-fluorothiobenzoyl)-4-oxo-10-methyl-HPI

2-(4-fluorothiobenzoyl)-4-oxo-11-methyl-HPI

2-(4-fluorothiobenzoyl)-4-oxo-11b-methyl-HPI

EXAMPLE 17

6.06 g. 4-oxo-HPI and 2.5 g. thioacetamide are heated, while stirring,for 3 hours at 140° C. After the usual working up of the reactionmixture, there is obtained 2-thioacetyl-4-oxo-HPI which, afterrecrystallization from ethanol, melts at 133° C.

The following compounds are obtained in an analogous manner from theappropriate thioamides and the appropriate compounds unsubstituted inthe 2-position:

2-cyclohexylthiocarbonyl-4-oxo-HPI; m.p. 180°-181° C.

2-cyclohexylthiocarbonyl-3-methyl-4-oxo-HPI

2-cyclohexylthiocarbonyl-4-oxo-6-cis-methyl-HPI

2-cyclohexylthiocarbonyl-4-oxo-6-trans-methyl-HPI

2-cyclohexylthiocarbonyl-4-oxo-7-methyl-HPI2-cyclohexylthiocarbonyl-4-oxo-8-methyl-HPI

2-cyclohexylthiocarbonyl-4-oxo-9-methyl-HPI

2-cyclohexylthiocarbonyl-4-oxo-10-methyl-HPI

2-cyclohexylthiocarbonyl-4-oxo-11-methyl-HPI

2-cyclohexylthiocarbonyl-4-oxo-11b-methyl-HPI

2-(pyridyl-3-thiocarbonyl)-4-oxo-HPI; m.p. 158° C.

2-(pyridyl-3-thiocarbonyl)-3-methyl-4-oxo-HPI

2-(pyridyl-3-thiocarbonyl)-4-oxo-6-cis-methyl-HPI

2-(pyridyl-3-thiocarbonyl)-4-oxo-6-trans-methyl-HPI

2-(pyridyl-3-thiocarbonyl)-4-oxo-7-methyl-HPI

2-(pyridyl-3-thiocarbonyl)-4-oxo-8-methyl-HPI

2-(pyridyl-3-thiocarbonyl)-4-oxo-9-methyl-HPI

2-(pyridyl-3-thiocarbonyl)-4-oxo-10-methyl-HPI

2-(pyridyl-3-thiocarbonyl)-4-oxo-11-methyl-HPI

2-(pyridyl-3-thiocarbonyl)-4-oxo-11b-methyl-HPI

2-(pyridyl-4-thiocarbonyl)-4-oxo-HPI; m.p. 190° C.

2-(pyridyl-4-thiocarbonyl)-3-methyl-4-oxo-HPI

2-(pyridyl-4-thiocarbonyl)-4-oxo-6-cis-methyl-HPI

2-(pyridyl-4-thiocarbonyl)-4-oxo-trans-methyl-HPI

2-(pyridyl-4-thiocarbonyl)-4-oxo-7-methyl-HPI

2-(pyridyl-4-thiocarbonyl)-4-oxo-8-methyl-HPI

2-(pyridyl-4-thiocarbonyl)-4-oxo-9-methyl-HPI

2-(pyridyl-4-thiocarbonyl)-4-oxo-10-methyl-HPI

2-(pyridyl-4-thiocarbonyl)-4-oxo-11-methyl-HPI

2-(pyridyl-4-thiocarbonyl)-4-oxo-11b-methyl-HPI.

EXAMPLE 18

3.7 g. cyclohexyl chloroformate in 20 ml. dichloromethane are added at20° C. to a solution of 4.04 g. 4-oxo-HPI and 2 g. triethylamine in 80ml. dichloromethane and the reaction mixture then stirred for an hour at20° C. After the usual working up, there is obtained2-cyclohexyloxycarbonyl-4-oxo-HPI, which melts at 105°-106° C.

The following compounds are obtained in an analogous manner, with theuse of the appropriate chloroformic acid esters:

2-methoxycarbonyl-4-oxo-HPI

2-ethoxycarbonyl-4-oxo-HPI; m.p. 78° C.

2-ethoxycarbonyl-3-methyl-4-oxo-HPI

2-ethoxycarbonyl-4-oxo-6-cis-methyl-HPI

2-ethoxycarbonyl-4-oxo-6-trans-methyl-HPI

2-ethoxycarbonyl-4-oxo-7-methyl-HPI

2-ethoxycarbonyl-4-oxo-8-methyl-HPI

2-ethoxycarbonyl-4-oxo-9-methyl-HPI

2-ethoxycarbonyl-4-oxo-10-methyl-HPI

2-ethoxycarbonyl-4-oxo-11-methyl-HPI

2-ethoxycarbonyl-4-oxo-11b-methyl-HPI

2-n-propoxycarbonyl-4-oxo-HPI

2-n-butoxycarbonyl-4-oxo-HPI

2-cyclopentyloxycarbonyl-4-oxo-HPI

2-cyclohexyloxycarbonyl-3-methyl-4-oxo-HPI

2-cyclohexyloxycarbonyl-4-oxo-6-cis-methyl-HPI

2-cyclohexyloxycarbonyl-4-oxo-6-trans-methyl-HPI

2-cyclohexyloxycarbonyl-4-oxo-7-methyl-HPI

1-cyclohexyloxycarbonyl-4-oxo-8-methyl-HPI

2-cyclohexyloxycarbonyl-4-oxo-9-methyl-HPI

2-cyclohexyloxycarbonyl-4-oxo-10-methyl-HPI

2-cyclohexyloxycarbonyl-4-oxo-11-methyl-HPI

2-cyclohexyloxycarbonyl-4-oxo-11b-methyl-HPI

2-cyclohexyloxycarbonyl-4-oxo-HPI

2-phenoxycarbonyl-4-oxo-HPI; m.p. 136°-137° C.

the parasitological action of the new compounds according to the presentinvention is described in more detail in the following:

EXAMPLE OF USE Action against Hymenolepis nana (in mice), Hymenolepismicrostoma (in mice) and Hymenolepis diminuta (in rats).

Experimental animals which had been infected with H. nana, H. microstomaor H. diminuta were treated after the expiry of the prepatence of theparasites. The active compound used was administered orally orsubcutaneously as an aqueous suspension.

The degree of action of the preparation was determined in that, aftersacrifice of the experimental animal, the remaining worms were counted,in comparison with untreated control animals, from which was calculatedthe percentage activity.

The compounds set out in the following Table show the indicatedeffectiveness against the above-mentioned parasites:

                  TABLE                                                           ______________________________________                                                                  Effective minimum                                                             dosage in mg/kg                                                               (parasite reduction                                 Active Compound                                                                              parasite   > 90%)                                              ______________________________________                                        2-benzoyl-4-oxo-6-                                                                          H. nana     25                                                  trans-methyl-HPI                                                                            H. microstoma                                                                             50                                                                H. diminuta 50                                                  2-benzoyl-4-oxo-6-                                                                          H. nana     50                                                  cis-methyl-HPI                                                                2-benzoyl-4-oxo-7-                                                                          H. nana     25                                                  methyl-HPI                                                                    2-(4-aminobenzoyl)-4-                                                                       H. nana     50                                                  oxo-6-cis-methyl-HPI                                                                        H. microstoma                                                                             50                                                  2-(3-nitrobenzoyl)-4-                                                                       H. nana     50                                                  oxo-6-cis-methyl-HPI                                                          2-cyclohexylcarbonyl-                                                                       H. nana     50                                                  4-oxo-6-trans-methyl-                                                                       H. microstoma                                                                             50                                                  HPI           H. diminuta 50                                                  2-cyclohexylcarbonyl-                                                                       H. nana     50                                                  4-oxo-8(or 11)-amino-                                                         HPI                                                                           2-(cyclohex-3-en-yl-                                                                        H. nana     50                                                  carbonyl)-4-oxo-6-                                                            cis-methyl-HPI                                                                2-thiobenzoyl-4-oxo-                                                                        H. nana     50                                                  HPI           H. microstoma                                                                             50                                                                H. diminuta 50                                                  2-(pyridyl-3-thio-                                                                          H. nana     50                                                  carbonyl)-4-oxo-HPI                                                           Quinacrine    H. diminuta >1000                                               Miclosamide   H. nana     500                                                               H. microstoma                                                                             500                                                 Dichlorophen  H. nana     >1000                                                             H. diminuta 500                                                 ______________________________________                                    

The active materials of general Formula I can be formulated intopharmaceutical compositions according to the methods known from theliterature, as the following Examples demonstrate:

EXAMPLE A Tablets for combating cestodes (adult)

a. Tablets containing 500 mg. 2-benzoyl-4-oxo-7-methyl-HPI as activecompound are prepared by working up a powder mixture which consists of 5kg. 2-benzoyl-4-oxo-7-methyl-HPI, 3-kg. lactose, 1.8 kg. maize starchand 0.2 kg. magnesium stearate.

b. The same mixture can be used for the production of tablets whichcontain 50, 250 and 1000 mg. 2-benzoyl-4-oxo-7-methyl-HPI.

The tablets containing 250 and 500 mg. 2-benzoyl-4-oxo-7-methyl-HPI asactive compound are preferably used for human medicine. All of theabove-mentioned tablets can be used for veterinary medicinal purposes.

EXAMPLE B. Tablets preferable for combating cestode hydatids andSchistosomes

a. Effervescent tablets

Each tablet contains:

    ______________________________________                                        2-benzoyl-4-oxo-7-methyl-HPI                                                                    1000 mg.                                                    citric acid       800 mg.                                                     sodium carbonate  900 mg.                                                     saccharin         5 mg.                                                       saccharose        ad 4000 mg.                                                 ______________________________________                                    

b. Sugared chewing tablets

Each tablet contains:

    ______________________________________                                        2-benzoyl-4-oxo-7-methyl-HPI                                                                    2000 mg.                                                    cellulose         80 mg.                                                      sodium carboxymethylcellulose                                                                   40 mg.                                                      coloring and aroma materials                                                                    as desired                                                  saccharose        ad 4000 mg.                                                 ______________________________________                                    

EXAMPLE C Dragees for combating cestodes in human medicine

Each dragee core contains:

    ______________________________________                                        2-benzoyl-4-oxo-7-methyl-HPI                                                                        250 mg.                                                 lactose               150 mg.                                                 maize starch           90 mg.                                                 magnesium stearate     10 mg.                                                 ______________________________________                                    

The dragee coating consists of talc, saccharose, titanium dioxide,calcium carbonate, polyvinyl-pyrrolidone, methyl cellulose, glycerol,magnesium oxide and lacquer.

This formulation can also be used for dragees which contain 500 mg.2-benzoyl-4-oxo-7-methyl-HPI as active compound.

EXAMPLE D Syrup for combating cestodes (human medicine)

The syrup is made by preparing a suspension of:

    ______________________________________                                        2-benzoyl-4-oxo-7-methyl-HPI                                                                         3.5 kg.                                                distilled water        2 liters                                               buffer                 0.1 liters                                             glycerol               3 kg.                                                  sorbitol               3 kg.                                                  saccharose            53 kg.                                                  mixture of 60% methyl p-hydroxy-                                              benzoate and 40% propyl p-                                                    hydroxy-benzoate       0.1 kg.                                                ethanol               12 liters                                               ______________________________________                                    

The mixture is admixed with coloring and aroma materials and made up to100 liters with distilled water.

EXAMPLE E Capsules for combating cestodes and Schistosomes in human andveterinary medicine.

Capsules of appropriate size are filled with a mixture of:

    ______________________________________                                        2-benzoyl-4-oxo-7-methyl-HPI                                                                        5000 mg.                                                talc                   250 mg.                                                magnesium stearate     150 mg.                                                ______________________________________                                    

Capsules containing 1000 mg. and 10,000 mg. of the active compound areprepared in the same way.

EXAMPLE F Injection liquid for human and veterinary medicinal purposes.

For subcutaneous administration in oily or aqueous suspension, 15 mg.ampoules are filled with a solution of 500 mg.2-benzoyl-4-oxo-7-methyl-HPI in 6 ml. water and 4 ml. propylene glycol,with the addition of a solubilizing agent. The ampoules areheat-sterilized or are provided with a preservation agent.

Similar ampoules are produced containing 100 mg.2-benzoyl-4-oxo-7-methyl-HPI (for small animals) and 1000 mg.2-benzoyl-4-oxo-7-methyl-HPI (for large animals).

EXAMPLE G Pellets

A powder mixture is produced from equal parts by weight of2-benzoyl-4-oxo-7-methyl-HPI and lactose which mixture, together withsodium carboxymethyl-cellulose, is worked up in the usual manner to givea uniform granulate with an average particle size of 1.5 mm.

EXAMPLE H Veterinary medicinal pre-mixture which is suitable, with afeedstuff as carrier, for further mixing to a medicated feed.

a. 25% pre-mixture (preferably for larger animals)

25 kg. 2-benzoyl-4-oxo-7-methyl-HPI are mixed with 75 kg. fine bran(wheat after millings) and/or lactose.

b. 5% pre-mixture (preferably for smaller animals)

5 kg. 2-benzoyl-4-oxo-7-methyl-HPI are worked up in a manner analogousto (a) above.

c. Example of a use of the pre-mixture according to a) above forcombating Moniezia types in bovine intestines.

In order to obtain a suitable medicated feed, 1 kg. of the pre-mixtureproduced according to a) above is mixed with 9 kg. of a conventionalfeed concentrate. 400 g. of this medicated feed, containing 10,000 mg.2-benzoyl-4-oxo-7-methyl-HPI are administered for combating Monieziainfection in adult cattle.

Analogously to Examples A to H, instead of 2-benzoyl-4-oxo-7-methyl-HPI,there can also be used the other active materials for general formula(I) or other physiologically compatible acid-addition salts for thepreparation of pharmaceutical compositions.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A compound of the formula ##STR7## wherein R¹ isa hydrogen atom, hydroxy or alkyl; R² is ##STR8## R³ is a hydrogen atom,alkyl or hydroxyalkyl; R⁴ is a hydrogen atom, alkyl or phenyl; R⁵ is anoxygen atom, two hydrogen atoms, or a hydrogen atom and one of alkyl,phenyl, halogen atoms, or hydroxy; R⁶ and R⁷, which can be alike ordifferent, each are a hydrogen atom, a halogen atom, hydroxy, amino,nitro, cyano, alkyl, alkoxy, alkanoyl, monoalkylamino, dialkylamino,alkanoylamino, or benzoyloxy; R⁸ is a hydrogen atom or alkyl; R⁹ iscycloalkyl or cycloalkenyl of 5 to 7 carbon atoms which is unsubstitutedor, substituted by a carbonyl oxygen atom X and Y, which can be the sameor different, each is an oxygen or sulfur atom; with the proviso that R²is ##STR9## when R¹ and R³ to R⁸, inclusive, each are hydrogen atoms andX is an oxygen atom alkyl, hydroxyalkyl, alkoxy and alkanoyl being up to4 carbon atoms.
 2. The compound of claim 1,2-cyclohexylcarbonyl-4-oxo-6-trans-methyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.3. The compound of claim 1, 2-cyclohexylcarbonyl-4-oxo-8(or11)-amino-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.
 4. Thecompound of claim 1,2-cyclohexylcarbonyl-4-oxo-11b-methyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.5. A compound of claim 1 wherein R² is ##STR10## and R⁹ is cyclohexyl orcyclohexenyl.
 6. A compound of claim 5 wherein R⁹ is cyclohexyl.
 7. Acompound of claim 1 wherein R¹ is hydrogen, R³ is hydrogen or methyl, R⁴is hydrogen or methyl, R⁵ represents two hydrogen atoms, or a hydrogenatom and a methyl group, one of R⁶ and R⁷ is hydrogen and the other ishydrogen, amino, nitro or chlorine, R⁸ is hydrogen and R⁹ is cyclohexyl.8. A compound of claim 1,1-methyl-2-cyclohexylcarbonyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.9. A compound of claim 1,2-cyclohexylcarbonyl-3-methyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.10. A compound of claim 1,2-cyclohexylcarbonyl-4-oxo-6-cis-methyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.11. A compound of claim 1,2-cyclohexylcarbonyl-4-oxo-7-methyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.12. A compound of claim 1, 2-cyclohexylcarbonyl-4-oxo-8(or11)-amino-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.
 13. Acompound of claim 1, 2-cyclohexylcarbonyl-4-oxo-8(or11)-chloro-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.
 14. Acompound of claim 1,2-(cyclohexene-4-carbonyl)-4-oxo-6-trans-methyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.15. A compound of claim 1,2-(cyclohexene-4-carbonyl)-4-oxo-11b-methyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.16. A compound of claim 1,2-cyclohexyl-thiocarbonyl-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.17. An anthelmintic composition comprising an anthelmintically effectiveamount per unit dosage of at least one compound of claim 1 in admixturewith a pharmaceutically acceptable carrier or in admixture with ananimal feed or feed concentrate.
 18. An anthelmintic compositionaccording to claim 17 adapted for oral administration.
 19. Ananthelmintic composition according to claim 17, in capsule form.
 20. Amethod of treating helminthiasis which comprises administering to theinfested patient an anthelmintically effective amount of at least onecompound of claim
 1. 21. A method of claim 20 wherein the patient ishuman.
 22. A method of claim 20 wherein the patient is animal.